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Anti-tumour effects of beta-sitosterol are mediated by AMPK/PTEN/HSP90 axis in AGS human gastric adenocarcinoma cells and xenograft mouse models
Abstract
We investigated the anti-cancer effects of beta-sitosterol (BS), a plant-derived sterol in AGS human gastric adenocarcinoma cells and xenograft mouse models. BS significantly reduced cell viability by inducing apoptosis in AGS adenocarcinoma cells. This was accompanied by the formation of apoptotic bodies, as detected by Annexin V, caspase 3/7 activity, and MitoPotential assay. BS stimulated phosphatase and tensin homolog (PTEN) and phospho-AMP-activated protein kinase (p-AMPK) expression. Pharmacological inhibitors or siRNA were used to further analyse the relationship between the two proteins. AMPK was found to represent a likely upstream regulator of PTEN. Additionally, two-dimensional gel electrophoresis was used to identify related proteins in the treatment of BS. The decrease of Hsp90 protein by BS was observed. Induction of PTEN protein and reduction of Hsp90 was mediated by AICAR, an AMPK activator, indicating that AMPK is necessary for PTEN and Hsp90 expression. Additionally, BS was found to be effective through the regulation of cancer biomarker. Furthermore, BS suppressed tumour growth without toxicity in the AGS xenograft mouse models-. Taken together, the present results demonstrate that BS exerts anti-cancer effects in AGS cells and xenograft mouse models by mediating AMPK, PTEN, and Hsp90.
... Epidemiological data indicate that people with diabetes have a high chance of being affected by cancers. Despite so many clinical studies, the available preclinical studies, such as in vitro, in vivo, and epidemiological studies, detailed how effectively β-sitosterol contributes to the deterrence and treatment of cancer (Ditty & Ezhilarasan, 2021;Shin et al., 2018) and diabetes Ponnulakshmi et al., 2019). Like other natural compounds, β-sitosterol has systemic biological activity and multitarget effectiveness. ...
... According to research, β-sitosterol caused apoptosis and reduced cell viability in AGS human gastric adenocarcinoma cells. Apoptotic cells were spotted using Caspase-3/7 activity, Annexin V, and the MitoPotential test (Shin et al., 2018). Additionally, phosphorylated adenosine monophosphate (AMP)-activated protein kinase (p-AMPK) and phosphatase and tensin homolog (PTEN) expression were increased due to the presence of β-sitosterol in the liver cells, and AMPK was identified as a possible PTEN upstream regulator. ...
... β-Sitosterol and its anticancer mechanism in gastric cancer cells may be connected to the PI3K/AKT/mTOR pathway-induced autophagy (Shin et al., 2018;Sun et al., 2019). Almost all types of tumors exhibit abnormal cell cycle activity, leading to tumor cell proliferation (Suski et al., 2021). ...
Sitosterol is a major bioactive constituent and the most abundant phytosterol in nuts, seeds, and vegetable oils. It is structurally similar to cholesterol, except for the addition of the ethyl group. The primary benefit of β‐sitosterol is that it lowers the body's absorption of low‐density lipoprotein, or “bad” cholesterol. Research efforts to date and information from the available literature have demonstrated that β‐sitosterol has many pharmacological benefits to improve human health; it effectively prevents heart diseases, cancer, and diabetes. To date, many investigations on β‐sitosterol have been conducted in in vitro and in vivo studies. There are considerable research gaps because there are almost no clinical studies to examine the safety and effectiveness of β‐sitosterol for various human diseases. This review aims to discuss the dietary sources and variations of β‐sitosterol in food crops and how it can successfully prevent cancer and diabetes, including the mechanism underlying these benefits. In addition, we also discuss the research gaps and provide our perspective on future research to propose β‐sitosterol as a nutraceutical candidate to prevent human diseases.
... Data were collected from the gene expression omnibus (GEO) and the cancer genome atlas databases. Multiple statistical analyses like differential gene expression and Kaplan-Meier survival were performed to assess the importance of LEF-1 in colon cancer (Shin et al., 2018). The findings revealed that LEF-1 levels were higher in colon cancer tissues and correlated with worse patient outcomes; elevated LEF-1 was also associated with the activation of the Wnt/β-catenin signaling pathway. ...
... Cancer cells often exhibit uncontrolled growth, marked by their ability to evade regular cell cycle checkpoints, leading to unchecked proliferation and often forming malignant tumors; the invasiveness of these cells is further accentuated by TRPM2-mediated Ca 2+ signaling, which has been implicated in promoting cell migration and potentially contributing to metastasis, underscoring the critical role of calcium channels in the aggressive behavior of certain cancer types (Ali et al., 2023). β-sitosterol was demonstrated to inhibit the growth and invasiveness of the human colon cancer cell line, HCT116; this inhibitory action was found to be mediated by down-regulating LEF-1 and thereby disrupting the Wnt/β-catenin pathway (Shin et al., 2018). ...
... This research suggests that by targeting LEF-1 with β-sitosterol, one could potentially inhibit the Wnt/β-catenin pathway and provide a novel treatment approach for colon cancer (Shin et al., 2018). When it comes to apoptosis, β-sitosterol functions through various mechanisms. ...
Sterols, including β‐sitosterol, are essential components of cellular membranes in both plant and animal cells. Despite being a major phytosterol in various plant materials, comprehensive scientific knowledge regarding the properties of β‐sitosterol and its potential applications is essential for scholarly pursuits and utilization purposes. β‐sitosterol shares similar chemical characteristics with cholesterol and exhibits several pharmacological activities without major toxicity. This study aims to bridge the gap between phytochemistry and current pharmacological evidence of β‐sitosterol, focusing on its anticancer activity and other biomedical properties. The goal is to provide a comprehensive understanding of β‐sitosterol's potential for future translational approaches. A thorough examination of the literature was conducted to gather relevant information on the biological properties of β‐sitosterol, particularly its anticancer therapeutic potential. Various databases were searched, including PubMed/MedLine, Scopus, Google Scholar, and Web of Science using appropriate keywords. Studies investigating the effects of β‐sitosterol on different types of cancer were analyzed, focusing on mechanisms of action, pharmacological screening, and chemosensitizing properties. Modern pharmacological screening studies have revealed the potential anticancer therapeutic properties of β‐sitosterol against various types of cancer, including leukemia, lung, stomach, breast, colon, ovarian, and prostate cancer. β‐sitosterol has demonstrated chemosensitizing effects on cancer cells, interfering with multiple cell signaling pathways involved in proliferation, cell cycle arrest, apoptosis, survival, metastasis invasion, angiogenesis, and inflammation. Structural derivatives of β‐sitosterol have also shown anti‐cancer effects. However, research in the field of drug delivery and the detailed mode of action of β‐sitosterol‐mediated anticancer activities remains limited. β‐sitosterol, as a non‐toxic compound with significant pharmacological potential, exhibits promising anticancer effects against various cancer types. Despite being relatively less potent than conventional cancer chemotherapeutics, β‐sitosterol holds potential as a safe and effective nutraceutical against cancer. Further comprehensive studies are recommended to explore the biological properties of β‐sitosterol, including its mode of action, and develop novel formulations for its potential use in cancer treatment. This review provides a foundation for future investigations and highlights the need for further research on β‐sitosterol as a potent superfood in combating cancer.
... β-sitosterol inhibits cell growth by inducing apoptosis in human gastric cancer SGC-7901 . β-sitosterol can mediate the AMPK/PTEN/Hsp90 pathway to inhibit the growth of human gastric cancer AGS cells in vitro and in vivo (Shin et al., 2018). Moreover, it also inhibits the proliferation of human colon cancer (HT-29) cells by stimulating the sphingolipid cycle (Khan et al., 2022). ...
... In colon cancer, β-sitosterol decreases the expression of proliferating cell nuclear antigen (PCNA) (Sharmila and Sindhu, 2017). Shin et al. observed that the antitumor effects of β-sitosterol are mediated by the AMPK/PTEN/HSP90 axis in AGS human gastric adenocarcinoma cells and xenograft mouse models (Shin et al., 2018). Wang et al. observed that β-sitosterol inhibited the proliferation of colorectal cancer cells by regulating the reactive oxygen species (ROS)/AMPK/mTOR pathway to inhibit colorectal cancer cell proliferation . ...
Cancer has become one of the major causes of human death. Several anticancer drugs are available; howeve their use and efficacy are limited by the toxic side effects and drug resistance caused by their continuous application. Many natural products have antitumor effects with low toxicity and fewer adverse effects. Moreover, they play an important role in enhancing the cytotoxicity of chemotherapeutic agents, reducing toxic side effects, and reversing chemoresistance. Consequently, natural drugs are being applied as potential therapeutic options in the field of antitumor treatment. As natural medicinal plants, some components of ginseng have been shown to have excellent efficacy and a good safety profile for cancer treatment. The pharmacological activities and possible mechanisms of action of ginseng have been identified. Its broad range of pharmacological activities includes antitumor, antibacterial, anti-inflammatory, antioxidant, anti-stress, anti-fibrotic, central nervous system modulating, cardioprotective, and immune-enhancing effects. Numerous studies have also shown that throuth multiple pathways, ginseng and its active ingredients exert antitumor effects on gastrointestinal (GI) tract tumors, such as esophageal, gastric, colorectal, liver, and pancreatic cancers. Herein, we introduced the main components of ginseng, including ginsenosides, polysaccharides, and sterols, etc., and reviewed the mechanism of action and research progress of ginseng in the treatment of various GI tumors. Futhermore, the pathways of action of the main components of ginseng are discussed in depth to promote the clinical development and application of ginseng in the field of anti-GI tumors.
... The bioactivity of avocado phytosterols has also been reported. For example, β-sitosterol has shown antiproliferative effects through induction of apoptosis of human gastric adenocarcinoma cells, with the formation of apoptotic bodies and induced expression of phosphatase and tensin homolog (PTEN) and phospho-AMP activated protein kinase (p-AMPK) (Shin et al., 2018;Villa-Rodriguez et al., 2020). These results were found in human gastric adenocarcinoma cells (AGS) and xenograft mouse models with no apparent toxicity (Shin et al., 2018). ...
... For example, β-sitosterol has shown antiproliferative effects through induction of apoptosis of human gastric adenocarcinoma cells, with the formation of apoptotic bodies and induced expression of phosphatase and tensin homolog (PTEN) and phospho-AMP activated protein kinase (p-AMPK) (Shin et al., 2018;Villa-Rodriguez et al., 2020). These results were found in human gastric adenocarcinoma cells (AGS) and xenograft mouse models with no apparent toxicity (Shin et al., 2018). Stigmast-5en-3-ol was reported as the main phytosterol (59%) in avocado seed, in addition to others including campesterol, stigmasterol and β-sitosterol (Alkhalf et al., 2019). ...
The increased demand for avocado, and therefore production and consumption, generate large quantities of by-products such as seeds, peel, and defatted pulp, which account for approximately 30% of fruit weight, and which are commonly discarded and wasted. The present review focuses on various compounds present in avocado fruit and its by-products, with particular interest to those that can be potentially used in different industrial forms, such as nutraceuticals, to add to or to formulate functional foods, among other uses. Main molecular families of bioactive compounds present in avocado include phenolic compounds (such as hydroxycinnamic acids, hydroxybenzoic acids, flavonoids and proanthocyanins), acetogenins, phytosterols, carotenoids and alkaloids. Types, contents, and possible functions of these bioactive compounds are described from a chemical, biological, and functional approach. The use of avocado and its by-products requires using processing methods that allow highest yield with the least amount of unusable residues, while also preserving the integrity of bioactive compounds of interest. Avocado cultivar, fruit development, ripening stage, and processing methods are some of the main factors that influence the type and amount of extractable molecules. The phytochemical diversity of avocado fruit and its by-products make them potential sources of nutraceutical compounds, from which functional foods can be obtained, as well as other applications in food, health, pigment, and material sectors, among others.
... Solubility of β-sitosterol is low that restricts its use (AbuMweis et al. 2014;Yin et al. 2018). Based on the best available evidence in literature, various pharmacological properties for phytosterol have been studied (Wilt et al. 1999;Shin et al. 2018;Yin et al. 2018). β-sitosterol applies its anti-tumor properties via MPK/PTEN/HSP90 axis in AGS human gastric adenocarcinoma cells (Shin et al. 2018). ...
... Based on the best available evidence in literature, various pharmacological properties for phytosterol have been studied (Wilt et al. 1999;Shin et al. 2018;Yin et al. 2018). β-sitosterol applies its anti-tumor properties via MPK/PTEN/HSP90 axis in AGS human gastric adenocarcinoma cells (Shin et al. 2018). Antioxidant and anti-inflammatory effects of β-sitosterol derivatives on acute hepatic injury was reported by Yin et al. (2018). ...
Objective. Polycystic ovary syndrome (PCOS) is a common and multifactorial disease associated with female factor infertility. Ulmus minor bark (UMB) is one of the medicinal plants used in Persian folklore as a fertility enhancer. In the current study, we aimed to elucidate the effect of UMB hydro-alcoholic extract on histological parameters and testosterone condition in an experimental model of PCOS rats.
Methods. Thirty female rats were randomly divided into five groups: (1) control, (2) vehicle, (3) PCOS/50 mg [6 mg/kg dehydroepiandrosterone (DHEA) + 50 mg/kg UMB hydro-alcoholic extract], (4) PCOS/150 mg (6 mg/kg DHEA + 150 mg/kg UMB hydro-alcoholic extract), and (5) PCOS (6 mg/kg DHEA). All interventions were performed for 21 days. Afterwards, stereological analysis was done for determination of ovarian volume and follicle number. The serum level of testosterone was measured by ELISA kit.
Results. UMB hydro-alcoholic extract improved the total number of the corpus luteum in the treatment groups when compared to the PCOS group (p<0.05). PCOS/150 mg and PCOS/50 mg groups showed significantly lower total number of the primordial, primary, and secondary follicles as well as testosterone level compared to the PCOS group (p<0.05). The total number of antral follicles and volume of ovary did not differ significantly between groups.
Conclusion. UMB extract may be an effective and good alternative in improving PCOS histo-logical and testosterone disturbances although further studies are warranted to confirm the safety of UMB plant in human.
... Particularly, stigmasterol could reduce COX-2 and CSF-1 [76]. Moreover, β-sitosterol could inhibit tumor weight and volume according in AGS xenograft animal study [78]. ...
... In vitro and in vivo [53,54] β-Sitosterol Anti-melanoma effect ↓JNK In vitro [77] Anti-gastric cancer effect ↑PTEN/p-AMPK In vitro and in vivo [78] nAChR: nicotinic acetylcholine receptor; NO: nitric oxide; NOD: nucleotidebinding domain; NQO1: NAD(P)H-quinone oxidoreductase 1; OV: opisthorchis viverrini; OVA: ovalbumin; OVA sIgE: OVA-specific immunoglobulin E; PE: petroleum ether; PET-CT: positron emission tomography-computed tomography; PGE2: prostaglandin E2; PIF: proteolysis-inducing factor; PMACI: phorbol 12-myristate 13-acetate and calcium ionophore A23187; PMBA: phenylenepolymethylene-bis-ammonium; PTEN: phosphatase and tensin homolog; SuCh: succinylcholine; TFF2: trefoil factor2; TLR4: toll like receptor 4; TNF-α: tumor necrosis factor-α; UGT : uridine 5′-iphospho-glucuronosyltransferases; VCAM-1: vascular cell adhesion molecule-1; VEGF: vascular endothelial growth factor. ...
Abstract Atractylodes lancea Thunb. DC. (AL) has a long history as one of the important herbs used in East Asia. This review is on the purpose of providing a comprehensive summary of the pharmacological effects of AL and its extractions. The publication from PubMed, ScienceDirect, Springer, and Wiley database was collected and summarized. The potential application of AL on the disease could be attributed to its pharmacological properties such as anti-cancer, anti-inflammatory and other essential effects. Hence, this review aims at providing evidence of the pharmacological activities of AL as one of natural products used in clinical trial.
... This can help increase cellular uptake and control the releasing profile. It seems that BBR-NL has good potential and can be a suitable drug delivery candidate [75,76]. The blood counts of hemoglobin and platelets decreased, but the number of white blood cells increased significantly. ...
Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, demands innovative therapeutic strategies to improve patient outcomes and quality of life. Addressing this urgent need, our study focuses on developing a berberine (BBR)-loaded nanoliposome (NL) as a targeted drug delivery system to combat GBM. Synthesized using the thin film hydration method and characterized through advanced physical and spectroscopic techniques, these NLs demonstrate promising potential in enhancing BBR’s therapeutic efficacy. The NL formulation achieved an impressive loading efficiency of 65.71 ± 1.31% with a particle size of 83 ± 12 nm, ensuring optimal delivery. Sustained release experiments revealed that 82.65 ± 1.75% of the encapsulated BBR was consistently released over 48 h, highlighting its controlled release capabilities. In vitro assays, including cell viability, TUNEL, and western blot analysis, confirmed the potent anti-cancer effects of NL-BBR. The formulation significantly disrupted the metabolism of U-87 glioblastoma cells, inducing enhanced autophagy and apoptosis, ultimately leading to cell death via intrinsic apoptotic pathways. Additionally, western blot results demonstrated that NL-BBR effectively suppressed the mitogen-activated protein kinase signaling pathway, a critical driver of GBM progression. This study underscores the transformative potential of incorporating BBR into NLs, which not only enhances its solubility and bioavailability but also significantly amplifies its therapeutic impact. These findings pave the way for advanced nano-based interventions in GBM treatment, offering a glimmer of hope for improved outcomes in this challenging cancer landscape.
... 54 β-sitosterol induces apoptosis in GC AGS cells by up-regulating the expression of PTEN and phospho-AMPK (p-AMPK), while down-regulating Hsp90 protein. 55 Autophagy serves to maintain cellular homeostasis by facilitating lysosomal degradation and the removal of damaged organelles, thereby promoting cell survival. However, under conditions of excessive cellular stress, autophagy can promote cell death. ...
Gastrointestinal (GI) cancer stands as one of the most prevalent forms of cancer globally, presenting a substantial medical and economic burden on cancer treatment. Despite advancements in therapies, it continues to exhibit the second highest mortality rate, primarily attributed to drug resistance and post-treatment side effects. There is an urgent need for novel therapeutic approaches to tackle this persistent challenge. Scutellaria baicalensis, widely used in Traditional Chinese Medicine (TCM), holds a profound pharmaceutical legacy. Modern pharmacological studies have unveiled its anticancer, antioxidant, and immune-enhancing properties. S. baicalensis contains hundreds of active ingredients, with flavonoids, polysaccharides, phenylethanoid glycosides, terpenoids, and sterols being the principal components. These constituents contribute to the treatment of GI cancer by inducing apoptosis in tumor cells, arresting the cell cycle, inhibiting tumor proliferation and metastasis, regulating the tumor microenvironment, modulating epigenetics, and reversing drug resistance. Furthermore, the utilization of modern drug delivery technologies can enhance the bioavailability and therapeutic efficacy of TCM. The treatment of GI cancer with S. baicalensis is characterized by its multi-component, multi-target, and multi-pathway advantages, and S. baicalensis has a broad prospect of becoming a clinical adjuvant or even the main therapy for GI cancer.
... In addition, ginkgolic acid (Fig. 5, an active ingredient in Ginkgo biloba L.) and periplocin (Fig. 5, a plant-derived glycoside) diminished the growth and development of PANC-1 and BxPC-3 cell lines in vitro models of pancreatic cancer by suppressing lipogenesis, promoting apoptosis, and activating AMPK-mTOR signaling [234,235]. In similar studies, panduratin A (Fig. 5, a major active ingredient isolated from Boesenbergia rotunda) [236], bixin (Fig. 5, an apocarotenoid extracted from Bixa orellana) [237], β-sitosterol (Fig. 5, an active phytosterol) [238], physciosporin (Fig. 5, a natural constituent obtained from Pseudocyphellaria faveolata) [239], hydroxycitric acid (Fig. 5, a derivative of citric acid in Garcinia cambogia) [240], and isogambogenic acid (Fig. 5, an active component from Garcinia hanburyi) [241], showed remarkable antineoplastic effects against numerous in vitro models of cancer, including melanoma, glioma, colorectal, breast, leukemia, and gastric adenocarcinoma, by diminishing metastasis, mitochondrial respiration, aerobic glycolysis, EMT, cancer metabolism, and cell proliferation by disrupting AMPK/ PGC-1α, mTOR, and AMPK and interconnected signaling pathways. Table 4 presents miscellaneous phytochemicals targeting AMPK/PGC-1α in cancer. ...
Background
Due to the complex pathophysiological mechanisms involved in cancer progression and metastasis, current therapeutic approaches lack efficacy and have significant adverse effects. Therefore, it is essential to establish novel strategies for combating cancer. Phytochemicals, which possess multiple biological activities, such as antioxidant, anti-inflammatory, antimutagenic, immunomodulatory, antiproliferative, anti-angiogenesis, and antimetastatic properties, can regulate cancer progression and interfere in various stages of cancer development by suppressing various signaling pathways.
Methods
The current systematic and comprehensive review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria, using electronic databases, including PubMed, Scopus, and Science Direct, until the end of December 2023. After excluding unrelated articles, 111 related articles were included in this systematic review.
Results
In this current review, the major signaling pathways of cancer metabolism are highlighted with the promising anticancer role of phytochemicals. This was through their ability to regulate the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. The AMPK/PGC-1α signaling pathway plays a crucial role in cancer cell metabolism via targeting energy homeostasis and mitochondria biogenesis, glucose oxidation, and fatty acid oxidation, thereby generating ATP for cell growth. As a result, targeting this signaling pathway may represent a novel approach to cancer treatment. Accordingly, alkaloids, phenolic compounds, terpene/terpenoids, and miscellaneous phytochemicals have been introduced as promising anticancer agents by regulating the AMPK/PGC-1α signaling pathway. Novel delivery systems of phytochemicals targeting the AMPK/PGC-1α pathway in combating cancer are also highlighted in this review.
... Recent studies have shown that β-sitosterol can exhibit anti-pancreatic cancer activity by modulating apoptosis and inhibiting epithelial-mesenchymal transition (EMT) by deactivating Akt/GSK-3β signaling [16]. β-Sitosterol exerts anticancer effects on AGS cells and xenograft mouse models by mediating AMPK, PTEN, and Hsp90 [17]. Furthermore, β-sitosterol can significantly inhibit the growth of A549 cells and trigger apoptosis via ROS-mediated mitochondrial dysregulation [18]. ...
Glioma is characterized by rapid cell proliferation, aggressive invasion, altered apoptosis and a poor prognosis. β-Sitosterol, a kind of phytosterol, has been shown to possess anticancer activities. Our current study aims to investigate the effects of β-sitosterol on gliomas and reveal the underlying mechanisms. Our results show that β-sitosterol effectively inhibits the growth of U87 cells by inhibiting proliferation and inducing G2/M phase arrest and apoptosis. In addition, β-sitosterol inhibits migration by downregulating markers of epithelial-mesenchymal transition (EMT). Mechanistically, network pharmacology and transcriptomics approaches illustrate that the EGFR/MAPK signaling pathway may be responsible for the inhibitory effect of β-sitosterol on glioma. Afterward, the results show that β-sitosterol effectively suppresses the EGFR/MAPK signaling pathway. Moreover, β-sitosterol significantly inhibits tumor growth in a U87 xenograft nude mouse model. β-Sitosterol inhibits U87 cell proliferation and migration and induces apoptosis and cell cycle arrest in U87 cells by blocking the EGFR/MAPK signaling pathway. These results suggest that β-sitosterol may be a promising therapeutic agent for the treatment of glioma.
... Luteolin regulates GC cells through multiple signaling pathways [75], exhibiting anti-proliferative and chemosensitizing effects [76]. Beta-sitosterol has shown preliminary validation of its effect on gastric tissue cells in a mouse model [77]. Nobiletin primarily exerts anti-proliferative effects on GC cells, inducing apoptosis and disrupting the cell cycle [78]. ...
Purpose
The aim of this study is to determine the effectiveness and reliability of adding traditional Chinese medicine in the clinical intervention for chronic atrophic gastritis through meta-analysis and network pharmacology verification.
Methods
A predefined search strategy was used to retrieve literature from PubMed, Embase database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wang Fang Data, and China Science and Technology Journal Database (VIP). After applying inclusion and exclusion criteria, a total of 12 randomized controlled trials were included for meta-analysis to provide clinical evidence of the intervention effects. A network meta-analysis using Bayesian networks was conducted to observe the relative effects of different intervention measures and possible ranking of effects. The composition of the traditional Chinese medicine formulation in the experimental group was analyzed, and association rule mining was performed to identify hub herbal medicines. Target genes for chronic atrophic gastritis were searched in GeneCards, Online Mendelian Inheritance in Man, PharmGkb, Therapeutic Target Database, and DrugBank. A regulatory network was constructed to connect the target genes with active ingredients of the hub herbal medicines. Enrichment analyses were performed using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to examine the central targets from a comprehensive viewpoint. Protein-Protein Interaction (PPI) networks were constructed to identify hub genes and conduct molecular docking with differentially expressed genes and corresponding active molecules.
Results
A total of 1,140 participants from 12 randomized controlled trials were included in the statistical analysis, confirming that the experimental group receiving the addition of traditional Chinese medicine (TCM) intervention had better clinical efficacy. Seven hub TCMs (White Peony Root, Largehead Atractylodes Rhizome, Pinellia Tuber, Tangerine Peel, Root of Pilose Asiabell, Danshen Root, and Coptis Root) were identified through association rule analysis of all included TCMs. Thirteen core hub genes (CDKN1A, CASP3, STAT1, TP53, JUN, MAPK1, STAT3, MAPK3, MYC, HIF1A, FOS, MAPK14, AKT1) were obtained from 90 gene PPI networks. Differential gene expression analysis between the disease and normal gastric tissue identified FOS and JUN as the significant genes. Molecular docking analysis revealed that Baicalein, Quercetin, Tanshinone iia, Kaempferol, Luteolin, Beta-sitosterol, and Nobiletin were the main active compounds with good binding activities to the two hub targets. GO analysis demonstrated the function of the targets in protein binding, while KEGG analysis indicated their involvement in important pathways related to cancer.
Conclusion
The study indicates that TCM intervention can improve the clinical treatment efficacy of chronic atrophic gastritis (CAG). The identified hub genes and hub TCM targets not only reveal the mechanisms of action of the active components of the TCMs, but also provide support for the development of new drugs, ultimately blocking the progression from chronic gastritis to gastric cancer.
... BS also inhibits Hsp90, a chaperone protein that is associated with apoptosis. Due to its role in stabilizing cell proliferation, cell cycle progression and other proteins required for survival [32] . BS could significantly inhibit the growth and induce apoptosis of human gastric cancer cells in vitro by reducing BCL2/Bax ratio and DNA damage [33] . ...
... Ajayi et al. [130] showed that Benzo[A] Pyrene induces oxidative stress, pro-inflammatory cytokines, expression of nuclear factor-kappa B, and deregulation of Wnt/β-catenin signaling in colons of exposed mice. Sitosterol (Beta-sitosterol) suppresses tumor growth without toxicity in AGS xenograft mouse models and induces apoptosis in human gastric adenocarcinoma cells [131]. Sitosterol prevents lipid peroxidation and improves antioxidant status and histoarchitecture in rats with 1,2-dimethylhydrazineinduced colon cancer [132]. ...
Abstract
Background Detection of appropriate receptor proteins and drug agents are equally important in the case of drug
discovery and development for any disease. In this study, an attempt was made to explore colorectal cancer (CRC)
causing molecular signatures as receptors and drug agents as inhibitors by using integrated statistics and bioinformatics
approaches.
Methods To identify the important genes that are involved in the initiation and progression of CRC, four microarray
datasets (GSE9348, GSE110224, GSE23878, and GSE35279) and an RNA_Seq profiles (GSE50760) were downloaded
from the Gene Expression Omnibus database. The datasets were analyzed by a statistical r-package of LIMMA to identify
common differentially expressed genes (cDEGs). The key genes (KGs) of cDEGs were detected by using the five
topological measures in the protein–protein interaction network analysis. Then we performed in-silico validation for
CRC-causing KGs by using different web-tools and independent databases. We also disclosed the transcriptional and
post-transcriptional regulatory factors of KGs by interaction network analysis of KGs with transcription factors (TFs)
and micro-RNAs. Finally, we suggested our proposed KGs-guided computationally more effective candidate drug
molecules compared to other published drugs by cross-validation with the state-of-the-art alternatives of top-ranked
independent receptor proteins.
Results We identified 50 common differentially expressed genes (cDEGs) from five gene expression profile datasets,
where 31 cDEGs were downregulated, and the rest 19 were up-regulated. Then we identified 11 cDEGs (CXCL8, CEMIP,
MMP7, CA4, ADH1C, GUCA2A, GUCA2B, ZG16, CLCA4, MS4A12 and CLDN1) as the KGs. Different pertinent bioinformatic
analyses (box plot, survival probability curves, DNA methylation, correlation with immune infiltration levels, diseases-
KGs interaction, GO and KEGG pathways) based on independent databases directly or indirectly showed that these
KGs are significantly associated with CRC progression. We also detected four TFs proteins (FOXC1, YY1, GATA2 and
NFKB) and eight microRNAs (hsa-mir-16-5p, hsa-mir-195-5p, hsa-mir-203a-3p, hsa-mir-34a-5p, hsa-mir-107, hsa-mir-
27a-3p, hsa-mir-429, and hsa-mir-335-5p) as the key transcriptional and post-transcriptional regulators of KGs. Finally,
our proposed 15 molecular signatures including 11 KGs and 4 key TFs-proteins guided 9 small molecules (Cyclosporin A, Manzamine A, Cardidigin, Staurosporine, Benzo[A]Pyrene, Sitosterol, Nocardiopsis Sp, Troglitazone, and Riccardin D)
were recommended as the top-ranked candidate therapeutic agents for the treatment against CRC.
Conclusion The findings of this study recommended that our proposed target proteins and agents might be considered
as the potential diagnostic, prognostic and therapeutic signatures for CRC.
Keywords Colorectal cancer (CRC), Gene expression profiles, Receptor proteins, Drug agents, Integrated
bioinformatics analyses
... In the AGS xenograft mice models, β-sitosterol decreased tumor development without causing harm. By modulating AMPK, PTEN, and Hsp90, β-sitosterol has anti-cancer actions in AGS cells and xenograft mice models (Fig. 3) [142]. The anti-cancer mechanism in gastric cancer cells might be linked to β-sitosterol-induced autophagy through the PI3K/AKT/mTOR system [143]. ...
Currently, available therapeutic medications are both costly as well as not entirely promising in terms of potency. So, new candidates from natural resources are of research interest to find new alternative therapeutics. A well known combination is a β-sitosterol, a plant derived nutrient with anticancer properties against breast, prostate, colon, lung, stomach, and leukemia. Studies have shown that β-sitosterol interferes with multiple cell signaling pathways, including cell cycle, apoptosis, proliferation, survival, invasion, angiogenesis, metastasis, antiinflammatory, anticancer, hepatoprotective, antioxidant, cardioprotective, and antidiabetic effects have been discovered during pharmacological screening without significant toxicity. The pharmacokinetic profile of β-sitosterol has also been extensively investigated. However, a comprehensive review of the pharmacology, phytochemistry and analytical methods of β-sitosterol is desired. Because β-sitosterol is a significant component of most plant materials, humans use it for various reasons, and numerous β-sitosterol-containing products have been commercialized. To offset the low efficacy of β-sitosterol, designing β-sitosterol delivery for “cancer cellspecific” therapy holds great potential. Delivery of β-sitosterol via liposomes is a demonstration that has shown great promise. But further research has not progressed on the drug delivery of β-sitosterol or how it can enhance β-sitosterol mediated anti inflammatory activity, thus making β-sitosterol an orphan nutraceutical. Therefore, extensive research on β-sitosterol as an anticancer nutraceutical is recommended.
... Hence, targeting AMPK has become a new strategy for cancer prevention and treatment (36). Eun et al. reported that SIT, depending on its concentration, strengthens the phosphorylation level of AMPK, and the enhanced activity of AMPK after SIT intervention affects the growth and apoptosis of tumor cells (37). Specifically, SITelicited apoptosis in gastric cancer AGS cells was achieved through the AMPK activation-mediated expression of phosphatase and tensin homolog (PTEN) gene. ...
β-Sitosterol (SIT), a white powdery organic substance with a molecular formula of C29H50O, is one of the most abundant naturally occurring phytosterols in plants. With a chemical composition similar to that of cholesterol, SIT is applied in various fields such as medicine, agriculture, and chemical industries, owing to its unique biological and physicochemical properties. Modern pharmacological studies have elucidated good anti-tumor therapeutic effect activity of SIT, which mainly manifests as pro-apoptotic, anti-proliferative, anti-metastatic, anti-invasive, and chemosensitizing on tumor cells. In addition, SIT exerts an anti-tumor effect on multiple malignant tumors such as breast, gastric, lung, kidney, pancreatic, prostate, and other cancers. Further, SIT derivatives with structural modifications are promising anti-tumor drugs with significant anti-tumor effects. This review article focuses on recent studies relevant to the anti-tumor effects of SIT and summarizes its anti-tumor mechanism to provide a reference for the clinical treatment of malignant tumors and the development of novel anti-tumor drugs.
... It has also been reported that a higher intake of quercetin is associated with a decreased risk of developing GC 118 . β-Sitosterol suppresses the proliferation and survival capacity of GC cells through the modulation of AMPK, PTEN, heat shock protein 90 (HSP90), and caspase signaling 126 . ...
Gastric cancer (GC) is one of the most common and deadly malignant tumors worldwide. While the application of herbal drugs for GC treatment is increasing, the multicompound–multitarget pharmacological mechanisms involved are yet to be elucidated. By adopting a network pharmacology strategy, we investigated the properties of the anticancer herbal drug FDY003 against GC. We found that FDY003 reduced the viability of human GC cells and enhanced their chemosensitivity. We also identified 8 active phytochemical compounds in FDY003 that target 70 GC-associated genes and proteins. Gene ontology (GO) enrichment analysis suggested that the targets of FDY003 are involved in various cellular processes, such as cellular proliferation, survival, and death. We further identified various major FDY003 target GC-associated pathways, including PIK3-Akt, MAPK, Ras, HIF-1, ErbB, and p53 pathways. Taken together, the overall analysis presents insight at the systems level into the pharmacological activity of FDY003 against GC.
... In adjuvant therapy, the efficacy of gemcitabine, a standard chemotherapeutic agent was evidently increased when it was combined with BS (Cao et al., 2019). In previous studies, BS treatments inhibited the proliferation of lung, prostate, breast, gastric and colon cancer cell lines (Awad et al., 2001;Choi et al., 2003;Awad et al., 2008;Shin et al., 2018). Consistent with above studies, in this study, BS treatments dose-dependently caused cytotoxicity in HepG2 cells and these results suggest that regardless of cancer cell line, BS induces cytotoxicity. ...
Objective:
It is of interest to investigate the anti-proliferative effect of β-sitosterol (BS) on human hepatocellular carcinoma (HepG2) cell line.
Materials and methods:
β-sitosterol treatments (0.6 and 1.2 mM/ml) were done in HepG2 and after 24 hr, cell viability was evaluated by MTT assay. Reactive oxygen species (ROS) accumulating potential of BS was assessed by dichloro-dihydro-fluorescein diacetate staining. Morphology related to apoptosis was investigated by acridine orange and ethidium bromide dual staining. Cytochrome c and caspase 3 expressions were evaluated by immunofluorescence and western blot analyses.
Results:
β-sitosterol induced cytotoxicity (p<0.001) and intracellular ROS in HepG2 cells in a dose-dependent manner. BS treatments accumulated induced intracellular ROS accumulation which led to membrane damage and mitochondrial toxicity. At the molecular level, BS treatments induced cytochrome c release from mitochondria and enhanced the protein expressions (p<0.05 vs 0.6 mM/ml and p<0.001 vs 1.2 mM/ml) of both caspase 3 and cleaved caspase 3.
Conclusion:
β-sitosterol induced ROS accumulation which plays a critical role in apoptosis via the intrinsic pathway in HepG2 cells. The present investigation paves the way for further in vivo studies.
... Rhein could induce apoptosis of human GC SGC-7901 cells [29]. Betasitosterol has an antitumor effect in AGS human gastric adenocarcinoma cells and xenograft mouse models [30]. ese results are consistent with our predictions, suggesting that high-degree compounds might play an important role in the treatment of GC. e occurrence and development of the tumor is not only related to its own malignant proliferation but also closely related to TME [31]. ...
Background:
Tumor microenvironment (TME) takes a vital effect on the occurrence and development of cancer. Radix Rhei Et Rhizome (RRER, Da-Huang in pinyin), a classical Chinese herb, has been widely used in gastric cancer (GC) for many years in China. However, inadequate systematic studies have focused on the anti-GC effect of RRER in TME. This study intended to uncover the mechanism of it by network pharmacology.
Methods:
We collected compounds and targets of RRER from traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction. GC targets were obtained from GeneCards. Protein-protein interaction (PPI) network and RRER-GC-target network were built by STRING and Cytoscape 3.2.1. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID).
Results:
We obtained 92 compounds of RRER. A total of 10 key compounds and 20 key targets were selected by "RRER-GC-target network" topological analysis. GO analysis showed that the biological process mainly involved in response to the tumor necrosis factor, positive regulation of fibroblast proliferation, and DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest. Molecular functions included cyclin-dependent protein serine/threonine kinase activity, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, and transmembrane receptor protein tyrosine kinase activity. Cellular components mainly were centrosome, cell surface, and membrane. KEGG pathway enrichment results mainly involved in the p53 signaling pathway, estrogen signaling pathway, and regulation of lipolysis in adipocytes.
Conclusion:
This study explored the anti-GC mechanism of RRER from the perspective of TME based on network pharmacology, which contributed to the development and application of RRER.
... The RPR was reported that its active constituents could play an important role in inhibiting LC, 28 gastric carcinoma, 29 breast carcinoma, 30 pancreatic carcinoma, 31 and intestinal carcinoma. 32 However, previous studies mainly focused on the pharmaceutical effect of single component rather than the complex ingredients in RPR, which limits our understanding of ...
Objective
To systematically explore the pharmacological mechanism of Radix Paeoniae Rubra (RPR) against lung cancer (LC).
Methods
A network pharmacology approach, which involves active ingredients and target forecast, network construction, gene ontology and pathway enrichment, was employed in this research. In addition, the effect of Baicalein (BAI) in RPR on A549 cells was researched in vitro and in vivo.
Results
A total of 159 targets of the 29 active components in RPR were procured by pharmacokinetic parameters. The network analysis showed that β-sitosterol, baicalein, (+)-catechin, ellagic acid, stigmasterol, (2R, 3R)-4-methoxyl-distylin were the main ingredients and JUN, VEGFA, BCL2 were the hub targets of RPR in the treatment of LC. The functional enrichment analysis showed that RPR likely was useful to LC by regulating numerous pathways including Pathways in cancer, MAPK signaling pathway and so on. MTT results showed that 100μM, 200μM, 400μM of BAI had a time and dose-dependent inhibitory effect on A549 cells proliferation; Wound healing and transwell assays showed that 100μM, 200μM, 400μM of BAI could significantly restrain the migration and invasion of A549 cells; Flow cytometry assay results showed that 100μM, 200μM, 400μM of BAI could induce apoptosis of A549 cells. In vivo, BAI (50, 100 mg/kg) significantly inhibited tumor growth and promoted apoptosis of tumor cells compared with the control group.
Conclusion
BAI in RPR may exert anti-tumor effects by inhibiting the proliferation, migration and invasion of LC cells, and inducing the apoptosis of LC cells.
... Moreover, sitosterol (MOL042 OB=36.91%, DL=0.75, HL=5.37) has been shown antimigration in various lung cancer cell types [27][28][29]. Linoleate acetate (MOL008 OB = 42.10%, DL = 0.20, HL = 7.48) is used in the treatment of NSCLC to inhibit inflammatory factors COX, LOX and TNF-α in the TME, which were closely related to their immune activities [30,31]. ...
The clinical notably success of immunotherapy fosters an enthusiasm in developing drugs by enhancing antitumor immunity in the tumor microenvironment (TME). Epimedium, is a promising herbal medicine for tumor immunotherapy due to the pharmacological actions in immunological function modulation and antitumor. Here, we developed a novel systems pharmacology strategy to explore the polypharmacology mechanism of Epimedium involving in targeting TME of non-small cell lung cancer (NSCLC). This strategy integrates the active compounds screening, target predicting, network pharmacology analysis and onco-immune interacting to predict the potential active compounds that trigger the antitumor immunity. Icaritin (ICT), a major active ingredient of Epimedium, was predicted to have good drug-like properties and target immune microenvironment in NSCLC via regulating multiple targets and pathways. Then, we evidenced that the ICT effectively inhibited tumor growth in LLC tumor-bearing mice and increases the infiltration of CD8+ T cells in TME. In addition, we demonstrated that ICT promotes infiltration of CD8+ T cells in TME by downregulating the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulating chemotaxis (CXCL9 and CXCL10). Overall, the systems pharmacology strategy offers an important paradigm to understand the mechanism of polypharmacology of natural products targeting TME.
... Despite its potential as a lead compound for inhibitor development, no medicinal chemistry studies pertaining to AICAR have been reported. Instead, AICAR has been used as a probe for biological investigation of various pathways 189,190 . ...
The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous, ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates. Because many of these clients are overexpressed or become mutated during cancer progression, Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways simultaneously. The first discovered Hsp90 inhibitors, geldanamycin and radicicol, function by competitively binding to Hsp90's N-terminal binding site and inhibiting its ATPase activity. However, most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four isoforms. Consequently, alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition, isoform-selective inhibition, and the disruption of Hsp90 protein−protein interactions. Since the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex, along with various co-chaperones and immunophilins, the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.
... β-sitosterol inhibits tumor cell proliferation and activates the apoptotic pathway of various cancer cell lines. Cancer cell lines through which β-sitosterol exerts its anticancer activities include, breast, colon, lung, gastric, and prostate cancers [45]. In A549 cells, β-sitosterol target the enzyme Trx/Trx1 reductase to induce apoptosis through ROS and p53 activation [46]. ...
Globally, cancer has been identified as one of the leading causes of death in public health. Its etiology is based on consistent exposure to carcinogenic. Plant-derived anticancer compounds are known to be less toxic to the normal cells and are classified into acetylenic compounds, phenolics, terpenes, and phytosterols. Dicoma anomala is a perennial herb belonging to the family Asteraceae and is widely distributed in Sub-Saharan Africa and used in the treatment of cancer, malaria, fever, diabetes, ulcers, cold, and cough. This review aimed at highlighting the benefits of D. anomala in various therapeutic applications with special reference to the treatment of cancers and the mechanisms through which the plant-derived agents induce cell death.
... Previous studies have demonstrated that berberine and evodiamine, the major bioactive ingredients in ZJW, exhibit anti-cancer effects in gastric cancer by inhibiting proliferation and inducing apoptosis and autophagic cell death [36][37][38][39]. Other representative ingredients in ZJW, including baicalein, baicalin, wogonin, isorhamnetin, and beta-sitosterol, are also involved in the anti-gastric cancer effect [40][41][42][43][44]. Collectively, a series of studies involving the active ZJW ingredients have provided evidence for the efficacy of ZJW in the treatment of gastric cancer. ...
Background
Zuojinwan (ZJW) is a traditional Chinese prescription normally used for gastritis. Several studies indicated that it could fight against gastric cancer. This study was designed to determine the potential pharmacological mechanism of ZJW in the treatment of gastric cancer.
Material/Methods
Bioactive compounds and potential targets of ZJW and related genes of gastric cancer were retrieved from public databases. Pharmacological mechanisms including crucial ingredients, potential targets, and signaling pathways were determined using protein-protein interaction (PPI) and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Virtual docking was performed to validate the findings.
Results
Network analysis identified 47 active ZJW compounds, and 48 potential ZJW target genes linked to gastric cancer. Quercetin, beta-sitosterol, isorhamnetin, wogonin, and baicalein were identified as potential candidate agents. Our PPI analysis results combined with previously published results indicated that matrix metalloproteinases family members MMP9, MMP1, and MMP3 may play key roles in the anti-gastric cancer effect of ZJW. Molecular docking analysis showed that these crucial targets had good affinity for the representative components in ZJW. GO and KEGG enrichment analysis showed that ZJW target genes functioned in multiple pathways for treating gastric cancer, including interleukin-17 signaling and platinum drug resistance.
Conclusions
Our results illuminate the active ingredients, associated targets, biological processes, and signaling pathways of ZJW in the treatment of gastric cancer. This study enhances our understanding of the potential effects of ZJW in gastric cancer and demonstrates a feasible method for discovering potential drugs from Chinese medicinal formulas.
... For example, Kaempferol has a powerful anti-cancer effect against various cancer cell lines [14,15]. Beta-sitosterol suppresses tumor growth without toxicity in AGS xenograft mouse models and induces apoptosis in human gastric adenocarcinoma cells [16]. Stigmasterol was reported to reduce tumor growth, macrophage recruitment, and tumor angiogenesis in a cholangiocarcinoma xenograft model [17]. ...
Background
The aim of this study was to identify the bioactive ingredients of Huangqin-Baishao herb pair and to reveal its anti-cancer mechanisms through a pharmacology approach.
Material/Methods
Detailed information on compounds in the HQ-BS herb pair was obtained from the Traditional Chinese medicine systems pharmacology (TCMSP) and screened by the criteria of OB ≥30% and DL ≥0.18. A systematic drug targeting model (SysDT) was used for compound targets prediction, and then the targets were analyzed for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The protein-protein interaction (PPI) network of HQ-BS targets was constructed, after identifying core networks through Cytoscape plugins.
Results
We found 47 bioactive compounds of HQ-BS and 107 human-derived targets. A compound target network and a target signal pathway network were constructed and used for topological analysis. Kaempferol, beta-sitosterol, stigmasterol, wogonin, and oroxylin-a were identified as core compounds and pathways in cancer. The calcium signaling pathway, PI3K-Akt signaling pathway, TNF signaling pathway, chemical carcinogenesis, estrogen signaling pathway, proteoglycans in cancer, HIF-1 signaling pathway, thyroid hormone signaling pathway, VEGF signaling pathway, small cell lung cancer, prostate cancer, colorectal cancer, NOD-like receptor signaling pathway, and T cell receptor signaling pathway were found to be potential signals of HQ-BS in treating cancer. Through PPI network analysis, TNF signaling pathway, tryptophan metabolism, proteoglycans in cancer, cell cycle, and chemical carcinogenesis sub-networks were obtained.
Conclusions
HQ-BS contains various bioactive compounds, including flavonoids, phytosterols, and other compounds, and these compounds can inhibit or activate multiple targets and pathways against cancer.
... Among the identified compounds, β-sitosterol is reported to have pharmacological activities, including antihyperlipidemia, anti-inflammation and antitumor. [17][18][19][20][21] Moreover, β-sitosterol showed positive effect on endothelial cell migration. [22] Aristolone possessed radical scavenging activity, [23] and α-amyrin induced proliferation of human keratinocytes. ...
Patrinia scabiosifolia (PS) has bioactivities such as antitumor and anti‐inflammation effects. However, its effects on human skin physiological activities, such as skin regeneration and wound healing, remain unclear. In this study, we investigated the effects of absolute extracted from PS flower (PSF) on migration and proliferation of human dermal keratinocyte (HaCat). The yield of PSF absolute obtained by solvent extraction method was 0.105 % and its five constituents were found in GC/MS analysis. The PSF absolute induced the proliferation and migration of HaCats. The absolute increased the phosphorylation of serine/threonine‐specific protein kinase (Akt) and extracellular signal‐regulated kinase1/2 (Erk1/2) in HaCats. In addition, the absolute stimulated the outgrowth of collagen sprouting of HaCats. These results demonstrated, for the first time, that PSF absolute may have positive effects on skin regeneration and/or wound healing by inducing migration and proliferation of dermal keratinocytes via the Akt/Erk1/2 pathway. Therefore, PSF absolute may be a useful natural material for skin regeneration and/or wound healing.
... Phytosterol, which is called the key to life, can be used to prevent high cholesterol (Cleghorn et al. 2003;Desai et al. 2016;Tapiero et al. 2003), lower blood lipids (Pedro et al. 2017), anticancer (Ling and Jones 1995;Shahzad et al. 2017;Yin et al. 2018), anti-inflammatory (Kurano et al. 2018), anti-tumor (Shin et al. 2018), etc. So the pharmacokinetics and health-promoting uses of phytosterol have been reviewed in some papers (Moreau et al. 2018;Shahzad et al. 2017). ...
In this paper, a hybrid monolithic column with modified nanodiamond and 1-dodecene as co-monomers was prepared and applied to the online enrichment and purification of β-sitosterol in edible oil. The obtained monolithic column was characterized by scanning electron microscopy (SEM) and nitrogen adsorption–desorption isotherm measurement, which indicated that the monolith possessed characteristics of porous structure and high permeability. Under the optimum conditions for extraction and determination, the linear regression coefficient for β-sitosterol was 0.998; the limit of detection (LOD) and the limit of quantitation (LOQ) were 3.0 μg mL⁻¹ and 10.0 μg mL⁻¹, respectively; the relative standard deviation (RSD) of intra-day and inter-day assays for four edible oils were 2.33–6.58% and 3.24–6.94%, respectively. The recovery was in the range of 89.6–105.5%. The results showed that the hybrid monolithic column with high selectivity and good permeability were successfully used as online solid-phase extraction (SPE) column for determination of β-sitosterol in edible oil.
... Through 2D gel electrophoresis, these authors observed that BSS can decrease the expression of Hsp90 and, through AMPK and PTEN, regulate anticancer activities. 47 In 2013, Valerio et al. 48 used BSS together with cyclodextrin to pretreat J774A.1 macrophages. ...
β-Sitosterol is a well known phytosterol in plants, but owing to its poor solubility in typical media, determining its cellular mechanisms has been proven to be difficult. In this study, we investigated the anti-inflammatory activity of β-sitosterol (BSS) isolated from Moringa oleifera in two cell lines. Over a dose range of 7.5 to 30 μM, BSS dispersed well in the medium as nanoparticles with diameters of 50 ± 5 nm and suppressed the secretion of inflammatory factors from keratinocytes and macrophages induced by PGN, TNF-α, or LPS, such as TNF-α, IL-1β, IL-6, IL-8, and ROS, separately. In addition, BSS significantly reduced the expression of NLRP3, a key component of NLRP3 inflammasomes, and inhibited the activation of caspase-1. There was partial inhibition of NF-κB in macrophages. This is the first study to report an increase in the solubility of nearly water-insoluble phytosterols via the formation of nanoparticles and to delineate the formulation’s capacity to inhibit the signal transduction pathways of inflammation in macrophages.
Xiaotan Sanjie Formula (XTSJF), a traditional Chinese prescription, holds promising potential in addressing gastric cancer (GC). Despite this, the fundamental constituents and underlying mechanisms that define XTSJF’s attributes remain enigmatic. Against this backdrop, this study endeavors to unravel the latent mechanisms driving XTSJF’s impact on GC, leveraging the synergistic prowess of network pharmacology and molecular docking methodologies. To understand the potential mechanism of XTSJF against GC, this study used network pharmacology, molecular docking, and bioinformatics analytic methodologies. There are 135 active components where the active ingredients with a higher degree value are quercetin, β-sitosterol, naringenin, nobiletin, and kaempferol and 167 intersecting targets in which TP53, MAPK3, MAPK1, STAT3, and AKT1 were key targets were identified in XTSJF in the treatment of GC. According to GO and KEGG analyses, XTSJF is mostly involved in the positive control of transcription from the RNA polymerase II promoter, enzyme interaction, and other biological processes in GC. KEGG analysis shows that XTSJF treated GC primarily by regulating signaling pathways including the TNF, PI3K-Akt, and MAPK signaling pathways. According to the results of the PPI network and molecular docking, quercetin, β-sitosterol, naringenin, nobiletin, and kaempferol exhibit stronger affinity with TP53, MAPK3, MAPK1, STAT3, and AKT1. This study indicates the active components of XTSJF as well as its possible molecular mechanism against GC, and it serves as a foundation for future fundamental research.
Objective:
This study investigated how Radix Bupleuri-Radix Paeoniae Alba (BP) was active against hepatocellular carcinoma (HCC).
Methods:
Traditional Chinese medicine systems pharmacology (TCMSP) database was employed to determine the active ingredients of BP and potential targets against HCC. Molecular docking analysis verified the binding activity of PTEN with BP ingredients. H22 cells were used to establish an HCC model in male balb/c mice. Immunofluorescence staining, immunohistochemistry, flow cytometry, western blotting, enzyme-linked immunosorbent assay, and real-time quantitative PCR were used to study changes in proliferation, apoptosis, PTEN levels, inflammation, and T-cell differentiation in male balb/c mice.
Results:
The major active ingredients in BP were found to be quercetin, kaempferol, isorhamnetin, stigmasterol, and beta-sitosterol. Molecular docking demonstrated that these five active BP ingredients formed a stable complex with PTEN. BP exhibited an anti-tumor effect in our HCC mouse model. BP was found to increase the CD8+ and IFN-γ+/CD4+ T cell levels while decreasing the PD-1+/CD8+ T and Treg cell levels in HCC mice. BP up-regulated the IL-6, IFN-γ, and TNF-α levels but down-regulated the IL-10 levels in HCC mice. After PTEN knockdown, BP-induced effects were abrogated.
Conclusion:
BP influenced the immune microenvironment through activation of the PTEN/PD-L1 axis, protecting against HCC.
Background:
Compound Xiao-ai-fei honey ointment (CXHO) is an anticancer preparation with a long history in Uyghur folk medicine in China and has been used for the treatment of gastric cancer (GC) in Xinjiang, China. Nevertheless, the mechanism of its anticancer effect remains to be investigated.
Methods:
Bioactive ingredients of CXHO were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database. Target genes of ingredients were acquired via the PubChem and Swiss target prediction database. Gene expression profiling of GC was obtained from GSE54129 in the GEO database and analyzed using the limma package in R. The hub genes associated with CXHO in GC were validated using the TIMER2.0 database, GEPIA2 database and Auto Dock tools. The effect of CXHO on migration of GC cells was detected by Transwell chamber assay and Wound healing assay. The effect of CXHO on expression levels of MMP2/MMP9 and NF-κb, PI3K/AKT signaling pathway was detected by Western blot assay.
Results:
Forty-five bioactive ingredients and their 819 related genes were found. A total of 462 differentially expressed genes were identified between GC patients and healthy controls. Seventeen common target genes were identified as hub genes CXHO against GC. Among them, MMP2 and MMP9 were significantly associated with tumor immune infiltrates and had good binding affinity with effective ingredients. Moreover, we validated the mRNA and protein expression levels and prognostic value of MMP2 and MMP9 by different databases. In addition, Kyoto encyclopedia of genes and genomes and gene ontology analyses showed that the 17 common target genes were mainly involved in steroid hormone biosynthesis and cancer-related pathways. Experimental results showed that CXHO inhibited migration of GC cells and down regulated the expression levels of MMP2/MMP9, NF-κb. In addition, CXHO can inhibited PI3K/AKT signaling pathway.
Conclusion:
We identified and experimental validated 2 pivotal target genes of CXHO against GC and preliminarily analyzed the potential mechanisms by which CXHO inhibits the development of GC. All these findings support CXHO as a promising drug for the treatment of GC.
Cancer is one of the primary causes of death worldwide and its incidence continues to increase year by year. Despite significant advances in research, the search for effective and non-toxic preventive and therapeutic agents remains greatly important. Cancer is a multimodal disease, where various mechanisms play significant roles in its occurrence and progression. This highlights the need for multi-targeted approaches that are not only safe and inexpensive, but provide effective alternatives for current therapeutic regimens. Beta-sitosterol (SIT), the most abundant phytosterol found in various plant foods represents such an option. Preclinical evidence over the past few decades has overwhelmingly shown that SIT exhibits multiple anticancer activities against a wide range of cancers, including liver, cervical, colon, stomach, breast, lung, pancreatic, and prostate cancers, as well as leukemia, multiple myeloma, melanoma, and fibrosarcoma. In this article, we present the latest advances and perspectives on SIT - systematically summarizing its antitumor mechanisms of action into seven main sections and combining current challenges and prospects - for its use as a promising agent for cancer prevention and treatment. Specifically, SIT plays a role in cancer prevention and treatment mainly by enhancing apoptosis, inducing cell cycle arrest, bidirectionally regulating oxidative stress, improving metabolic reprogramming, inhibiting invasion and metastasis, modulating immunity and inflammation, and combating drug resistance. Although SIT holds such great promise, the poor aqueous solubility and bioavailability coupled with low targeting efficacy limit its therapeutic efficacy and clinical application. Further research on novel drug delivery systems may improve these deficiencies. Overall, through complex and pleiotropic mechanisms, SIT has good potential for tumor chemoprevention and chemotherapy. However, no clinical trials have yet proven this potential. This review provides theoretical basis and rationality for the further design and conduct of clinical trials to confirm the anticancer activity of SIT.
Differentiation-inducing factor 1 (DIF-1) is a morphogen produced by Dictyostelium discoideum that inhibits the proliferation and migration of both D. discoideum and most mammalian cells. Herein, we assessed the effect of DIF-1 on mitochondria, because DIF-3, which is similar to DIF-1, reportedly localizes in the mitochondria when added exogenously, however the significance of this localization remains unclear. Cofilin is an actin depolymerization factor that is activated by dephosphorylation at Ser-3. By regulating the actin cytoskeleton, cofilin induces mitochondrial fission, the first step in mitophagy. Here, we report that DIF-1 activates cofilin and induces mitochondrial fission and mitophagy mainly using human umbilical vein endothelial cells (HUVECs). AMP-activated kinase (AMPK), a downstream molecule of DIF-1 signaling, is required for cofilin activation. Pyridoxal phosphatase (PDXP)-known to directly dephosphorylate cofilin-is also required for the effect of DIF-1 on cofilin, indicating that DIF-1 activates cofilin through AMPK and PDXP. Cofilin knockdown inhibits mitochondrial fission and decreases mitofusin 2 (Mfn2) protein levels, a hallmark of mitophagy. Taken together, these results indicate that cofilin is required for DIF-1- induced mitochondrial fission and mitophagy.
Objective:
To explore the molecular biological mechanisms of Chinese herbal medicines for the treatment of gastric precancerous lesions by data mining and network pharmacology.
Methods:
The keywords "gastric precancerous lesions""gastric precancerous disease""gastric mucosal intraepithelial neoplasia""gastric mucosal heterogeneous hyperplasia""gastric precancerous state""chronic gastritis, atrophic""combined Chinese and Western medicine""Chinese medicine therapy""efficacy evaluation" "randomized controlled trial"were searched in China Journal Full-text Database, Wanfang Data, VIP database, PubMed and Embase from 2001 to 2021. The information was extracted from the literature which met the inclusion and exclusion criteria, and the database was constructed to identify the high-frequency herbal medicines. The top six Chinese herbal medicines were analyzed by the network pharmacology methods, including the acquisition of herbs compounds and gastric precancerous lesions targets using Pharmacology Database and Analysis Platform and GeneCards databases, construction of protein-protein interaction network, and screening of core targets, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of core targets through Metascape platform, etc., to elucidate their active components, targets and pathways.
Results:
A total of 482 compound prescriptions with 603 herbal medicines were included, and the top 6 herbal medicines with higher application frequency were Ume plum (63.35%), Curcuma longa (58.54%), Paeonia lactiflora (54.06%), Salvia miltiorrhiza (49.92%), Rhizoma alba (46.43%), and Astragalus membranaceus (45.44%). The results of the network pharmacological analysis showed that the active ingredients were 4 types from Ume plum, 3 from Curcuma longa, 9 from Paeonia lactiflora, 13 from Salvia miltiorrhiza, 7 from Astragalus alba, and 9 from Astragalus; 77 predicted targets were in Ume plum, 11 in Curcuma longa, 33 in Paeonia lactiflora, 58 in Salvia miltiorrhiza, 65 in Astragalus alba and 89 in Astragalus; and 98 crossover genes were obtained after these targets were compared with the disease genes, among which HSP90AA1, AKT1, TP53, STAT3, MAPK1 and TNF had higher relevance to the treatment of gastric precancerous lesions. The results of the GO enrichment analysis showed that the active ingredients of high frequency Chinese medicine mostly acted through biological processes such as response to inorganic substance, response to hormone, gland development, positive regulation of cell migration, positive regulation of cell motility, etc. The targets include cellular components such as vesicle lumen, secretory granule lumen, cytoplasmic vesicle lumen, transcription regulator complex, and with molecular functions such as kinase binding, protein kinase binding and DNA-binding transcription factor binding. The results of the KEGG pathway enrichment analysis showed that Paeonia lactiflora, Ulmus lucidus, Salvia miltiorrhiza and Astragalus mainly act through the cancer pathway and PI3K-AKT pathway; Curcuma longa and Rhizoma alba mainly act through the cancer pathway and proteoglycans in cancer, and all six herbs were involved in the cancer pathway and five herbs are involved in the PI3K-AKT pathway.
Conclusion:
In this study, we obtained the top 6 high-frequency Chinese herbal medicines in the treatment of gastric precancerous lesions by data mining method, and revealed that their mechanisms are involved in cell proliferation, differentiation, immunity, inflammation and other processes mainly through cancer pathway, PI3K-AKT signaling pathway, proteoglycans in cancer.
Apoptosis is a feature of progressions steatosis to nonalcoholic steatohepatitis (NASH) and can be explained by endoplasmic reticulum stress (ERS). The present study aimed to investigate the protective effects of plant sterol ester of α-linolenic acid (PS-ALA) on ERS-triggered apoptosis in high fat diet-fed mice and oleic acid-induced hepatocytes, and further explore the underlying mechanisms. Our results showed that PS-ALA improved NAFLD in both in vivo and in vitro models. Moreover, PS-ALA treatment can attenuate ERS and associated apoptosis via inhibiting IRE1α/TRAF2/JNK signal pathway. Furthermore, we found that the protective effect of PS-ALA on ERS-triggered apoptosis was mediated by activation of AMPK as pretreatment with Compound C, an AMPK inhibitor, abolished the anti-apoptotic effect of PS-ALA. Taken together, our results illustrate that PS-ALA attenuating ERS-mediated apoptosis via activating AMPK, which provided new insights into the protective effect of PS-ALA in NAFLD.
Makgeolli, a widely consumed traditional alcoholic beverage in Korea, is brewed mainly from rice using Nuruk as a fermentation starter, which contains fungi, yeast, and lactic acid bacteria. Among 58 Makgeolli samples brewed using various Nuruks, we found that one exhibited anti-obesity properties, with stachydrine shown to be responsible for these properties. Stachydrine promotes lipolysis and inhibits lipid accumulation in 3T3-L1 adipocytes; it also reduces weight gain and improves glucose tolerance and insulin resistance in a mouse model. Stachydrine dramatically suppresses adipsin mRNA levels in liver and adipose tissue, whereas serum adipsin levels were elevated in stachydrine-treated mice compared to mice fed a high-fat diet alone. Moreover, stachydrine recovers endoplasmic reticulum homeostasis and regulates adipsin expression. We highlight the potential use of stachydrine as a therapeutic agent for the treatment of obesity and insulin resistance and the use of Makgeolli fermented by Nuruk as a source of novel bioactive compounds.
•Of 58 Makgeolli samples, one was found to exhibit anti-obesity properties
•Stachydrine found to be responsible for the anti-obesity properties of Makgeolli
•Stachydrine promotes lipolysis and inhibits lipid accumulation in 3T3-L1 adipocytes
•Stachydrine mends endoplasmic reticulum homeostasis and regulates adipsin expression
•Stachydrine can be used to treat obesity and insulin resistance
The agro-industry generates huge amount of waste, which leads to major economic loss and pollution. Yet this waste can be considered as a ‘golden mine’ of bioactive compounds such as flavonoids, carotenoids, tocopherols, phytosterols, tannins, polysaccharides and dietary fibers. This waste can be converted into biofuels, nutraceuticals, oils and fibers for various sectors including cosmetics, food industry, pharmaceuticals, paper and energy. In particular, β-sitosterol is a well-known nutraceutical which can be extracted from side stream biomass of agroindustries, e.g. fruits pomace, seeds, seed oils, nuts and rum factories. β-sitosterol has been well tested at preclinical levels but clinical application is limited by sitosterol low bioavailability and half-life. Here we review the extraction, chemistry, pharmacology, and delivery of β-sitosterol to enhance its therapeutic efficacy.Keywordsβ-sitosterolAgro-industrial wastePhytosterolNutraceuticalConventional methodsNon-conventional methodsPharmacological activitiesNanocarriersDelivery systemPolymeric nanoparticlesLipid nanoparticles
Ethnopharmacological relevance
Banxia Xiexin Decoction (BXD) was first recorded in a Chinese medical classic, Treatise on Febrile Diseases and Miscellaneous Diseases, which was written in the Eastern Han dynasty of China. This ancient prescription consists of seven kinds of Chinese herbal medicine, namely, Pinellia ternata, Rhizoma Coptidis, Radix scutellariae, Rhizoma Zingiberis, Ginseng, Jujube, and Radix Glycyrrhizaepreparata. In clinic practice, its original application in China mainly has focused on the treatment of chronic gastritis for several hundred years. BXD is also effective in treating other gastrointestinal diseases (GIDs) in modern medical application. Despite available literature support and clinical experience, the treatment mechanisms or their relationships with the bioactive compounds in BXD responsible for its pharmacological actions, still need further explorations in more diversified channels. According to the analysis based on the five-flavor theory of TCM, BXD is traditionally viewed as the most representative prescription for pungent-dispersion, bitter-purgation and sweet-tonification. Consequently, based on the flavor-oriented analysis, the compositive herbs in BXD can be divided into three flavor groups, namely, the pungent, bitter, and sweet groups, each of which has specific active ingredients that are possibly relevant to GID treatment.
Aim of the review
This paper summarized recent literatures on BXD and its bioactive components used in GID treatment, and provided the pharmacological or chemical basis for the further exploration of the ancient prescription and the relative components.
Method
ology: Relevant literature was collected from various electronic databases such as Pubmed, Web of Science, and China National Knowledge Infrastructure (CNKI). Citations were based on peer-reviewed articles published in English or Chinese during the last decade.
Results
Multiple components were found in the pungent, bitter, and sweet groups in BXD. The corresponding bioactive components include gingerol, shogaol, stigmasterol, and β-sitosterol in the pungent group; berberine, palmatine, coptisine, baicalein, and baicalin in the bitter group; and ginsenosides, polysaccharides, liquiritin, and glycyrrhetinic acid in the sweet group. These components have been found directly or indirectly responsible for the remarkable effects of BXD on GID.
Conclusion
This review provided some valuable reference to further clarify BXD treatment for GID and their possible material basis, based on the perspective of the flavor-oriented analysis.
Beta sitosterol (BS) is a dietary phytosterol with promising therapeutic applications. The low bioavailability and rapid degradation of BS is the main challenges for their use in the food and pharmaceutical industries. Liposome mediated drug delivery systems are the useful approaches to improve the biopharmaceutical properties of BS. In this study, we had prepared nanoliposome encapsulated beta sitosterol (LBS) with improved bioavailability and stability. The prepared nanoliposomes had spherical vesicles, with mean particle size of 115 nm and had an encapsulation efficiency of 86%. Our in vitro results showed that LBS treatment could induce apoptosis in lymphoma cell lines as evidenced by acridine orange/ethidium bromide and nuclear staining. Our in vivo studies involving experimental tumor models revealed that LBS treatment could significantly (p < 0.01) reduce the tumor loads, improve the survival rate, and stabilize the body weights in Dalton's Lymphoma Ascites (DLA) tumor bearing mice when compared to BS. Hematological and serum biochemical parameters also improved significantly (p < 0.01) after LBS administration than free drug. The overall study results revealed that LBS exhibits promising therapeutic efficacy in comparison with non-encapsulated BS in regulating experimental tumor development as well as induction of lymphoma cell apoptosis.
Phytosterols and phytostanols are natural products present in vegetable oils, nuts, and seeds, or added to consumer food products whose intake is inversely associated with incidence and prognosis of several cancers. Randomized cancer prevention trials in humans are unfeasible due to time and cost yet the cellular processes and signaling cascades that underpin anti-cancer effects of these phytochemicals have been explored extensively in vitro and in preclinical in vivo models. Here we have performed an original systematic review, meta-analysis, and qualitative interpretation of literature published up to June 2020. MEDLINE, Scopus, and hand-searching identified 408 unique records that were screened leading to 32 original articles that had investigated the effects of phytosterols or phytostanols on cancer biology in preclinical models. Data was extracted from 22 publications for meta-analysis. Phytosterols were most commonly studied and found to reduce primary and metastatic tumor burden in all cancer sites evaluated. Expression of pAKT, and markers of metastasis (alkaline phosphatase, matrix metalloproteases, epithelial to mesenchymal transcription factors, lung and brain colonization), angiogenesis (vascular endothelial growth factor, CD31), and proliferation (Ki67, proliferating cell nuclear antigen) were consistently reduced by phytosterol treatment in breast and colorectal cancer. Very high dose treatment (equivalent to 0.2–1 g/kg body weight not easily achievable through diet or supplementation in humans) was associated with adverse events including poor gut health and intestinal adenoma development. Phytosterols and phytostanols are already clinically recommended for cardiovascular disease risk reduction, and represent promising anti-cancer agents that could be delivered in clinic and to the general population at low cost, with a well understood safety profile, and now with a robust understanding of mechanism-of-action.
Lucuma is a superfruit of Andean origin, with ovoid shape, greenish yellow color, nice smell and intense sweet taste. In recent years this superfruit has won great popularity in the international market, and its demand tends to increase exponentially in the future, due to its properties as a functional food for its bioactive components like β-carotens, niacin, phenolic components, phytosterols, among others that give this fruit beneficial properties for health, such as its anti-inflammatory action, antioxidant effect, antihypertensive action, antibacterial, energizing, healing, and its use as a natural sweetener. Currently, research is being carried out about its influence on metabolism, its antidiabetic, anti-cancer capacity and its use to prevent heart disease and counteract Alzheimer's. The properties of lucuma are still under study and greater benefits and applications are expected. The objective of this work was to announce the components and beneficial properties of lucuma known from the point of view of health.
Naturally derived drugs and plant-based products are attractive commodities that are being explored for cancer treatment. This in vitro study aimed to investigate the role of Hypericum triquetrifolium (50% ethanol: 50% water) extract (HTE) treatment on apoptosis, cell cycle modulation, and cell cycle arrest in human colon cancer cell line (HCT-116). HTE induced cell death via an apoptotic process, as assayed by an Annexin V-Cy3 assay. Exposing HCT-116 cells to 0.064, 0.125, 0.25, and 0.5 mg/mL of HTE for 24 h led to 50 ± 9%, 71.6 ± 8%, 85 ± 5%, and 96 ± 1.5% apoptotic cells, respectively. HCT-116 cells treated with 0.25 and 0.5 mg/mL HTE for 3 h resulted in 38.9 ± 1.5% and 57.2 ± 3% cleavage of caspase-3-specific substrate, respectively. RT-PCR analysis revealed that the HTE extract had no effect on mRNA levels of Apaf-1 and NOXA. Moreover, the addition of 0.125 mg/mL and 0.25 mg/mL HTE for 24 h was clearly shown to attenuate the cell cycle progression machinery in HCT-116 cells. GC/MS analysis of the extract identified 21 phytochemicals that are known as apoptosis inducers and cell cycle arrest agents. All the compounds detected are novel in H. triquetrifolium. These results suggest that HTE-induced apoptosis of human colon cells is mediated primarily through the caspase-dependent pathway. Thus, HTE appears to be a potent therapeutic agent for colon cancer treatment.
Naturally derived drugs and plant-based products are attractive commodities that are being explored for cancer treatment. This in vitro study aimed to investigate the role of Hypericum triquetrifolium (50% ethanol: 50% water) extract (HTE) treatment on apoptosis, cell cycle modulation, and cell cycle arrest in human colon cancer cell line (HCT-116). HTE induced cell death via an apoptotic process, as assayed by an Annexin V-Cy3 assay. Exposing HCT-116 cells to 0.064, 0.125, 0.25, and 0.5 mg/mL of HTE for 24 h led to 50 ± 9%, 71.6 ± 8%, 85 ± 5%, and 96 ± 1.5% apoptotic cells, respectively.
HCT-116 cells treated with 0.25 and 0.5 mg/mL HTE for 3 h resulted in 38.9 ± 1.5% and 57.2 ± 3% cleavage of caspase-3-specific substrate, respectively.
RT-PCR analysis revealed that the HTE extract had no effect on mRNA levels of Apaf-1 and NOXA. Moreover, the addition of 0.125 mg/mL and 0.25 mg/mL HTE for 24 h was clearly shown to attenuate the cell cycle progression machinery in HCT-116 cells.
GC/MS analysis of the extract identified 21 phytochemicals that are known as apoptosis inducers and cell cycle arrest agents. All the compounds detected are novel in H. triquetrifolium. These results suggest that HTE-induced apoptosis of human colon cells is mediated primarily through the caspase-dependent pathway. Thus, HTE appears to be a potent therapeutic agent for colon cancer treatment.
β-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial–mesenchymal transition (EMT) markers and AKT/GSK-3β signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM.
β-Sitosterol (BS), a major bioactive constituent present in plants and vegetables has shown potent anticancer effect against many human cancer cells, but the underlying mechanism remain elusive on NSCLC cancers. We found that BS significantly inhibited the growth of A549 cells without harming normal human lung and PBMC cells. Further, BS treatment triggered apoptosis via ROS mediated mitochondrial dysregulation as evidenced by caspase-3 & 9 activation, Annexin-V/PI positive cells, PARP inactivation, loss of MMP, Bcl-2-Bax ratio alteration and cytochrome c release. Moreover, generation of ROS species and subsequent DNA stand break were found upon BS treatment which was reversed by addition of ROS scavenger (NAC). Indeed BS treatment increased p53 expression and its phosphorylation at Ser15, while silencing the p53 expression by pifithrin-α, BS induced apoptosis was reduced in A549 cells. Furthermore, BS induced apoptosis was also observed in NCI-H460 cells (p53 wild) but not in the NCI-H23 cells (p53 mutant). Down-regulation of Trx/Trx1 reductase contributed to the BS induced ROS accumulation and mitochondrial mediated apoptotic cell death in A549 and NCI-H460 cells. Taken together, our findings provide evidence for the novel anti-cancer mechanism of BS which could be developed as a promising chemotherapeutic drug against NSCLC cancers.
The incitement of unfolded protein response (UPR) during endoplasmic reticulum (ER) stress by diverse intracellular (hypoxia, nutrient deprivation, etc.) or extracellular (environmental or drug induced) stimuli is considered a major threat for perturbing cellular homeostasis leading to gathering of unfolded proteins inside the cell. The catastrophic UPR events emerge as a foremost cellular adaptation by remodeling cancer cell signaling and restoring ER homeostasis in favor of tumor growth. The transient ER stress protects cancer cells from undergoing apoptosis, whereas the prolonged stress response further activates a number of cell death pathways. The present review summarizes the UPR mediated triggering of transcriptional and translational reprogramming, which will provide novel therapeutic strategies towards pro-death mechanisms rather than a cellular adaptation in tumorigenesis. Nonetheless, the current topic also thrashes out the reprogramming of emerging molecular switching events by complex UPR-mediated signaling to trigger apoptosis. Novel agents from various natural, semi-synthetic and synthetic sources that target ER stress signaling pathway to selectively modulate the UPR phenomena with preclinical efficacy are recapitulated. Since, major emphasis on ER stress-induced transcriptional and translational reprogramming remains to be explored, we believe that the current subject will instigate more attention from the biomedical researchers in this decisive research direction.
Despite the global decline in the incidence and mortality of gastric cancer, it remains one of the most common malignant tumors of the digestive system. Although surgical resection is the preferred treatment for gastric cancer, chemotherapy is the preferred treatment for recurrent and advanced gastric cancer patients who are not candidates for reoperation. The short overall survival and lack of a standard chemotherapy regimen make it important to identify novel treatment modalities for gastric cancer. Within the field of tumor biology, molecular targeted therapy has attracted substantial attention to improve the specificity of anti-cancer efficacy and significantly reduce non-selective resistance and toxicity. Multiple clinical studies have confirmed that molecular targeted therapy acts on various mechanisms of gastric cancer, such as the regulation of epidermal growth factor, angiogenesis, immuno-checkpoint blockade, the cell cycle, cell apoptosis, key enzymes, c-Met, mTOR signaling and insulin-like growth factor receptors, to exert a stronger anti-tumor effect. An in-depth understanding of the mechanisms that underlie molecular targeted therapies will provide new insights into gastric cancer treatment.
PTEN is the most important negative regulator of the PI3K signaling pathway. In addition to its canonical, PI3K inhibition-dependent functions, PTEN can also function as a tumor suppressor in a PI3K-independent manner. Indeed, the PTEN network regulates a broad spectrum of biological functions, modulating the flow of information from membrane-bound growth factor receptors to nuclear transcription factors, occurring in concert with other tumor suppressors and oncogenic signaling pathways. PTEN acts through its lipid and protein phosphatase activity and other non-enzymatic mechanisms. Studies conducted over the past 10 years have expanded our understanding of the biological role of PTEN, showing that in addition to its ability to regulate proliferation and cell survival, it also plays an intriguing role in regulating genomic stability, cell migration, stem cell self-renewal, and tumor microenvironment. Changes in PTEN protein levels, location, and enzymatic activity through various molecular mechanisms can generate a continuum of functional PTEN levels in inherited syndromes, sporadic cancers, and other diseases. PTEN activity can indeed, be modulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and post-translational modifications. This review will discuss our current understanding of the biological role of PTEN, how PTEN expression and activity are regulated, and the consequences of PTEN dysregulation in human malignant tumors.
Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.
Colorectal cancer, a leading cause of cancer death, has been linked to inflammation and obesity. Berberine, an isoquinoline alkaloid, possesses anti-inflammatory, anti-diabetes and anti-tumor properties. In the azoxymethane initiated and dextran sulfate sodium (AOM/DSS) promoted colorectal carcinogenesis mouse model, berberine treated mice showed a 60% reduction in tumor number (P = 0.009), a 48% reduction in tumors <2 mm, (P = 0.05); 94% reduction in tumors 2-4 mm, (P = 0.001), and 100% reduction in tumors >4 mm (P = 0.02) compared to vehicle treated mice. Berberine also decreased AOM/DSS induced Ki-67 and COX-2 expression. In vitro analysis showed that in addition to its anti-proliferation activity, berberine also induced apoptosis in colorectal cancer cell lines. Berberine activated AMP-activated protein kinase (AMPK), a major regulator of metabolic pathways, and inhibited mammalian target of rapamycin (mTOR), a downstream target of AMPK. Furthermore, 4E-binding protein-1 and p70 ribosomal S6 kinases, downstream targets of mTOR, were down regulated by berberine treatment. Berberine did not affect Liver kinase B1 (LKB1) activity or the mitogen-activated protein kinase pathway. Berberine inhibited Nuclear Factor kappa-B (NF-κB) activity, reduced the expression of cyclin D1 and survivin, induced phosphorylation of p53 and increased caspase-3 cleavage in vitro. Berberine inhibition of mTOR activity and p53 phosphorylation was found to be AMPK dependent, while inhibition NF-κB was AMPK independent. In vivo, berberine also activated AMPK, inhibited mTOR and p65 phosphorylation and activated caspase-3 cleavage. Our data suggests that berberine suppresses colon epithelial proliferation and tumorigenesis via AMPK dependent inhibition of mTOR activity and AMPK independent inhibition of NF-κB. © 2014 Wiley Periodicals, Inc.
Despite the advances in biomedical research and clinical applications, cancer remains a leading cause of death worldwide. Given the limitations of conventional chemotherapeutics, including serious toxicities and reduced quality of life for patients, the development of safe and efficacious alternatives with known mechanism of action is much needed. Prevention of cancer through dietary intervention may hold promise and has been investigated extensively in the recent years. AMP-activated protein kinase (AMPK) is an energy sensor that plays a key role in the regulation of protein and lipid metabolism in response to changes in fuel availability. When activated, AMPK promotes energy-producing catabolic pathways while inhibiting anabolic pathways, such as cell growth and proliferation - thereby antagonizing carcinogenesis. Other anti-cancer effects of AMPK may include promoting autophagy and DNA repair upon UVB damage. In the last decade, interest in AMPK has grown extensively as it emerged as an attractive target molecule for cancer prevention and treatment. Among the latest developments is the activation of AMPK by naturally occurring dietary constituents and plant products - termed phytochemicals. Owing to their efficacy and safety, phytochemicals are considered as an alternative to the conventional harmful chemotherapy. The rising popularity of using phytochemicals for cancer prevention and therapy is supported by a substantial progress in identifying the molecular pathways involved, including AMPK. In this article, we review the recent progress in this budding field that suggests AMPK as a new molecular target in the prevention and treatment of cancer by phytochemicals.
The identification of a complex containing the tumor suppressor LKB1 as the critical upstream kinase required for the activation of AMP-activated protein kinase (AMPK) by metabolic stress was reported in an article in Journal of Biology in 2003. This finding represented the first clear link between AMPK and cancer. Here we briefly discuss how this discovery came about, and describe some of the insights, especially into the role of AMPK in cancer, that have followed from it.
In September 2003, our groups published a joint paper [1] in Journal of Biology (now BMC Biology) that identified the long-sought and elusive upstream kinase acting on AMP-activated protein kinase (AMPK) as a complex containing LKB1, a known tumor suppressor. Similar findings were reported at about the same time by David Carling and Marian Carlson [2] and by Reuben Shaw and Lew Cantley [3]; at the time of writing these three papers have received between them a total of over 2,000 citations. These findings provided a direct link between a protein kinase, AMPK, which at the time was mainly associated with regulation of metabolism, and another protein kinase, LKB1, which was known from genetic studies to be a tumor suppressor. While the idea that cancer is in part a metabolic disorder (first suggested by Warburg in the 1920s [4]) is well recognized today [5], this was not the case in 2003, and our paper perhaps contributed towards its renaissance. The aim of this short review is to recall how we made the original finding, and to discuss some of the directions that these findings have taken the field in the ensuing ten years.
Heat shock protein 90 (HSP90), a molecular chaperone, has provoked great interest as a promising molecular target for cancer treatment, due to its involvement in regulating the conformation, stability and functions of key oncogenic proteins. At present, a variety of chemical compounds targeting HSP90 have been developed and have shown convincing anti-neoplastic activity in various preclinical tumor models. The aim of our study was to evaluate the antitumor effects of a novel HSP90 inhibitor, NVP-AUY922, in esophageal squamous cancer cells (ESCC). Four ESCC cell lines (TE-1, TE-4, TE-8, TE-10) were examined. NVP-AUY922 potently inhibited the proliferation of ESCC, particularly in PTEN-null TE-4 cells with a 2-3 times lower IC50 than the other three cell lines. Western blot analysis showed that PTEN-null TE-4 cells exhibited higher AKT and ERK activity, which contribute to cell proliferation and survival. NVP-AUY922 significantly suppressed the activity of AKT and ERK in TE-4 but not in PTEN-proficient TE-10 cells. Genetic modification experiments demonstrated that the sensitivity to NVP-AUY922 was decreased by exogenous transduction of PTEN in TE-4 and increased by silencing PTEN expression in intact PTEN-expressing TE-10, suggesting that the expression of PTEN may be associated with cell sensitivity in HSP90 inhibition. Furthermore, the enhanced activity of AKT in PTEN-silenced TE-10 was more easily suppressed by NVP-AUY922. Collectively, NVP-AUY922 exhibits a strong antiproliferative effect, revealing its potential as a novel therapeutic alternative to current ESCC treatment. The effect may be improved further by impeding PTEN expression.
Purpose: Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.
Experimental Design: Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.
Results: The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G2–M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.
Conclusion: We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment. Clin Cancer Res; 17(12); 3993–4005. ©2011 AACR.
While incidence and mortality rates for most cancers (including lung, colorectum, female breast, and prostate) are decreasing in the United States and many other western countries, they are increasing in several less developed and economically transitioning countries because of adoption of unhealthy western lifestyles such as smoking and physical inactivity and consumption of calorie-dense food. Indeed, the rates for lung and colon cancers in a few of these countries have already surpassed those in the United States and other western countries. Most developing countries also continue to be disproportionately affected by cancers related to infectious agents, such as cervix, liver, and stomach cancers. The proportion of new cancer cases diagnosed in less developed countries is projected to increase from about 56% of the world total in 2008 to more than 60% in 2030 because of the increasing trends in cancer rates and expected increases in life expectancy and growth of the population. In this review, we describe these changing global incidence and mortality patterns for select common cancers and the opportunities for cancer prevention in developing countries. Cancer Epidemiol Biomarkers Prev; 19(8); 1893–907. ©2010 AACR.
SNU (Seoul National University) cell lines have been established from Korean cancer patients since 1982. Of these 109 cell lines have been characterized and reported, i.e., 17 colorectal carcinoma, 12 hepatocellular carcinoma, 11 gastric carcinoma, 12 uterine cervical carcinoma, 17 B-lymphoblastoid cell lines derived from cancer patients, 5 ovarian carcinoma, 3 malignant mixed Mllerian tumor, 6 laryngeal squamous cell carcinoma, 7 renal cell carcinoma, 9 brain tumor, 6 biliary tract, and 4 pancreatic carcinoma cell lines. These SNU cell lines have been distributed to biomedical researchers domestic and worldwide through the KCLB (Korean Cell Line Bank), and have proven to be of value in various scientific research fields. The characteristics of these cell lines have been reported in over 180 international journals by our laboratory and by many other researchers from 1987. In this paper, the cellular and molecular characteristics of SNU human cancer cell lines are summarized according to their genetic and epigenetic alterations and functional analysis.
PTEN is a tumor suppressor gene that is frequently mutated in human tumors. It functions primarily as a lipid phosphatase and plays a key role in the regulation of phosphatidylinositol-3'-kinase. PTEN appears to play a crucial role in modulating apoptosis by reducing the levels of PtdIns(3,4,5)P3, a phospholipid that activates AKT, a central regulator of apoptosis. To understand the role of PTEN in regulating cell proliferation and apoptosis, we stably overexpressed PTEN in PC3 cells, which are prostate cancer cells that lack PTEN. Overexpression of PTEN in two different clones inhibited cell proliferation and increased serum starvation-induced apoptosis, as compared to control cells. Interestingly, PTEN overexpression resulted in a 44-60% reduction in total insulin-like growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression. [35S]methionine pulse experiments in PC3 cells overexpressing PTEN demonstrated that these cells synthesize significantly lower levels of the IGF-IR precursor, whereas PTEN overexpression had no effect on IGF-IR degradation. Taken together, our results show that PTEN can regulate cell proliferation and apoptosis through inhibition of IGF-IR synthesis. These results have important implications for understanding the roles of PTEN and the IGF-IR in prostate cancer cell tumorigenesis.
Peroxisome proliferator-activated receptors γ (PPARγ) exert diverse effects on cancer cells. Recent studies showed that rosiglitazone, a synthetic ligand for PPARγ, inhibits cell growth. However, the exact mechanisms underlying this effect are still being explored, and the relevance of these findings to lung cancer remains unclear. Here, we report that rosiglitazone reduced the phosphorylation of Akt and increased phosphatase and tensin homologue (PTEN) protein expression in non–small cell lung carcinoma (NSCLC) cells (H1792 and H1838), and this was associated with inhibition of NSCLC cell proliferation. These effects were blocked or diminished by GW9662, a specific PPARγ antagonist. However, transfection with a CMX-PPARγ2 overexpression vector restored the effects of rosiglitazone on Akt, PTEN, and cell growth in the presence of GW9662. In addition, rosiglitazone increased the phosphorylation of AMP-activated protein kinase α (AMPKα), a downstream kinase target for LKB1, whereas it decreased phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream target of mammalian target of rapamycin (mTOR). Of note, GW9662 did not affect the phosphorylation of AMPKα and p70S6K protein. The inhibitory effect of rosiglitazone on NSCLC cell growth was enhanced by the mTOR inhibitor rapamycin; however, it was blocked, in part, by the AMPKα small interfering RNA. Taken together, these findings show that rosiglitazone, via up-regulation of the PTEN/AMPK and down-regulation of the Akt/mTOR/p70S6K signal cascades, inhibits NSCLC cell proliferation through PPARγ-dependent and PPARγ-independent signals. [Mol Cancer Ther 2006;5(2):430–7]
These figures on phytosterols should he welcomed by dietitians and nutritionists concerned with planning fat-controlled diets and menus.
Liver cancer is a common malignant tumor associated with a short-survival period and high-mortality rate, and its prevalence in China is particularly high. This study aimed to investigate the effect of overexpressing the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene on liver cancer cell apoptosis and provide new insight into the treatment of this disease. The experimental design included four treatment groups, consisting of HHCC and H22 cells transfected with PTEN recombinant plasmids (HHCC+PTEN, H22+PTEN), and those transfected with control plasmids (HHCC+NC, H22+NC). The expression of PTEN mRNA was determined by quantitative polymerase chain reaction, and protein levels were examined by western blot. Cell apoptosis was measured using flow cytometry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling. PTEN mRNA expression in cells transfected with pcDNA3.1-PTEN was significantly increased compared to the control groups (P < 0.05). In addition, western blotting revealed PTEN protein expression in the treatment groups to be significantly elevated in comparison to control cells (P < 0.05). Flow cytometry showed that apoptosis rates of both HHCC+PTEN (approximately 21.9%) and H22+PTEN (approximately 41.0%) cells were significantly higher than those of the control groups (P < 0.05). Moreover, the difference in apoptosis rate between experimental and control groups was significant (P < 0.05). In this study, HHCC and H22 cells were successfully transfected with pcDNA3.1-PTEN in vitro. We conclude that overexpression of PTEN can effectively inhibit proliferation of these cells and promote their apoptosis.
The last decade has witnessed remarkable progress in the utilization of natural products for the prevention and treatment of human cancer. Many agents now in the pipeline for clinical trial testing have evolved from our understanding of how human nutritional patterns account for widespread differences in cancer risk. In this review, we have focused on many of these promising agents arguing that they may provide a new strategy for cancer control: natural products once thought to be only preventive in their mode of action now are being explored for efficacy in tandem with cancer therapeutics. Natural products may reduce off target toxicity of therapeutics while making cancers more amenable to therapy. On the horizon is the use of certain natural products, in their own right, as mitigants of late stage cancer, a new frontier for small molecule natural product drug discovery.
Resveratrol, a natural phenolic compound found in red grapes, has been reported to inhibit proliferation and induce apoptosis via regulation of AMPK signaling pathways in several cancer cell types. However, little is known about the effect of resveratrol on the human Nasopharyngeal carcinoma (NPC) cell line C666-1. Moreover, the molecular mechanisms of resveratrol-mediated apoptosis in C666-1 cells remain to be clarified.
Cell proliferation was measured by CCK8 assay, cell apoptosis rate was evaluated by flow cytometric analysis, and the protein expression alterations of AMPK signaling pathways were detected by Western blotting.
Treatment of resveratrol inhibited cell viability and promote apoptosis of C666-1 cells. In addition, we showed that resveratrol could also activate caspase-3 and alter the Bax/Bcl-2 apoptotic signaling. Furthermore, all these changes may be due to the activation of AMPK activity by resveratrol treatment, and we also found that the p70S6K and s6 activities, downstream factors of AMPK, were also blocked by resveratrol.
Our results revealed that resveratrol can be regarded as a new effective and chemopreventive compound for human NPC treatment.
Makgeolli is a traditional wine in Korea, and has been traditionally believed to exhibit health benefits. However, the inhibitory effect of dealcoholized Makgeolli on cancer has never been investigated scientifically. In this study, dealcoholized Makgeolli (MK) exhibited an anti-angiogenic effect by inhibiting tube formation in human umbilical vein endothelial cells (HUVECs) without cytotoxicity. Treatment with MK reduced the proliferation of AGS human gastric adenocarcinoma cells in a dose-dependent manner and increased the sub-G1 population. Next, we evaluated whether MK could induce apoptosis in AGS cells by using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay or Annexin V method. Treatment with MK at 500 and 1000 μg/mL increased the number of TUNEL-positive AGS cells. Under the same conditions, MK-treated (500 and 1000 μg/mL) cells showed significant induction of early or late apoptosis, compared to untreated cells (no induction). In addition, MK also induced phosphatase and tensin homolog (PTEN) expression in AGS cells. However, p53 expression in AGS cells was not changed by MK treatment. Furthermore, MK at 500 mg/(kg·day) reduced tumor size and volume in AGS tumor xenografts. Taken together, MK may be useful for the prevention of cancer cell growth.
Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. There are, however, distinct differences in incidence rates in different geographic regions. While the incidence rate of gastric cancer has been falling, that of gastric cardia cancers is reportedly on the rise in some regions. Helicobacter pylori (H. pylori) infection is a major risk factor of non-cardia gastric cancer, and data has emerged concerning the role of H. pylori eradication for primary prevention of gastric cancer. Dietary, lifestyle and metabolic factors have also been implicated. Although addressing these other factors may contribute to health, the actual impact in terms of cancer prevention is unclear. Once irreversible histological changes have occurred, endoscopic surveillance would be necessary. A molecular classification system offers hope for molecularly tailored, personalised therapies for gastric cancer, which may improve the prognosis for patients.
As part of the filtration barrier, podocytes play an important role in the development of diabetic nephropathy. Disturbances in insulin signaling accompanied by insulin resistance can lead to various intracellular events. We hypothesized that high glucose concentrations would lead to disturbances in interactions between AMPK and PTEN proteins in podocytes. Experiments were performed in primary rat podocytes cultured with normal (5.6mM) or high (30mM) glucose concentrations for 5 d. Immunodetection methods were used to detect AMPK, PTEN, insulin receptor, and Akt proteins, and their phosphorylated forms. Insulin-stimulated changes in glucose uptake were used to detect insulin resistance. Isoforms of AMPK were detected by RT-PCR. AMPK and PTEN activities were modified by metformin, Compound C, siRNA for AMPK isoforms α1 and α2 and siRNA for PTEN, respectively. We found that impairment of insulin induction of glucose uptake into podocytes cultivated in the presence of high glucose concentrations for long periods of time is associated with increased PTEN levels in an AMPK-dependent manner.
β-Sitosterol is the main dietary phytosterol found in plants and has been shown to inhibit proliferation and induce apoptosis in human solid tumors such as colon and breast cancers. However, the mechanism by which β-sitosterol induces apoptosis is not completely understood in leukemic cells. This study investigated the mechanism of apoptosis induced by β-sitosterol in human leukemic U937 cells. β-Sitosterol induced cytotoxicity and apoptosis in U937 cells in a concentration dependent manner, as measured by hemocytometer counts, fluorescence microscopy, agarose gel electrophoresis, and flow cytometry analysis. The increase in apoptosis induced by β-sitosterol was associated with down-regulation of Bcl-2, degradation of poly-(ADP-ribose) polymerase (PARP) and phospholipase C (PLC)-γ1 protein, and activation of caspase-3. β-Sitosterol induced apoptosis was not associated with changes in the expression of Bcl-xL, Bax, or inhibitor of apoptosis proteins (IAPs). z-DEVD-fmk, a caspase-3 specific inhibitor, blocked caspase-3 activation and PARP degradation, and significantly attenuated β-sitosterol-induced apoptosis. This suggests that caspase-3 activation is partially essential for β-sitosterol-induced apoptosis. Bcl-2 overexpression also significantly blocked caspase-3 activation and the decrease in PARP cleavage by β-sitosterol, and effectively attenuated the apoptotic response to β-sitosterol. These results show that β-sitosterol potently induces apoptosis in U937 cells and that β-sitosterol-induced apoptosis is related to the selective activation of caspase-3 and induction of Bax/Bcl-2 ratio.
Purpose:
To investigate the effects and the possible molecular mechanisms of metformin on HER2 positive breast cancer cells.
Methods:
SK-BR-3 HER2 positive breast cancer cells were treated with different concentrations of metformin. The growth inhibitory rate of the cells was calculated by MTT assay, apoptosis was detected by flow cytometry, and the expression level of heat shock protein 90 (HSP90) was performed by Western blot analysis. A control group consisted of cells treated with PBS.
Results:
With increased concentrations of metformin, cell growth inhibitory rates increased. The growth inhibitory rates with 0.5 mM, 2mM or 8mM metformin were significantly higher compared with the control group (p<0.05). Apoptosis in the metformin treated cells was also significantly higher compared with the control group (p=0.003). The expression level of HSP90 in the metformin group was significantly lower than that in the control group.
Conclusion:
Metformin can inhibit the proliferation and promote apoptosis of HER2 positive breast cancer cells,which is maybe related to inhibition of HSP90.
Heat Shock Protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment because of its role in stabilizing the active form of a wide range of client oncoproteins. This study investigated the mechanism of apoptosis induced by the purine-scaffold Hsp90 inhibitor PU-H71 in different human cancer cell lines and examined the role of Bcl-2 and Bax in this process. We demonstrated that Hsp90 inhibition by PU-H71 generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of Grp94, Grp78, ATF4 and CHOP. In response to PU-H71-induced ER stress, apoptosis was triggered in melanoma, cervix, colon, liver and lung cancer cells, but not in normal human fibroblasts. Apoptosis was executed through the mitochondrial pathway as shown by down-regulation of Bcl-2, up-regulation and activation of Bax, permeabilization of mitochondrial membranes, release of cytochrome c and activation of caspases. We also found that, in contrast to the ER stressor thapsigargin, PU-H71 induced apoptosis in cells overexpressing Bcl-2 and thus overcame the resistance conferred by this anti-apoptotic protein. In addition, although Bax deficiency rendered cells resistant to PU-H71, combined treatment with the anticancer drugs cisplatin or melphalan greatly sensitized these cells to PU-H71. Taken together, these data suggest that inhibition of Hsp90 by PU-H71 is a promising strategy for cancer treatment, particularly in the case of tumors resistant to conventional chemotherapy.
Mitogen-activated protein kinases (MAPKs) cascades play important roles in cell proliferation, death, and differentiation in response to external stimuli. However, the precise role of MAPKs in platycodin D (PD)-induced cytotoxicity remains unclear. In this study, we investigated the anticancer effect of PD and its underlying mechanism on AGS human gastric cancer cells. PD significantly inhibited cell proliferation and induced anoikis, which is a form of apoptosis in which cells detach from the substrate. It showed phosphatidylserine externalization, DNA fragmentation, increase of sub-G1 phase, and activation of caspases in a dose- and time-dependent manner. This apoptosis has been associated with the extrinsic pathway via Fas-L and the intrinsic pathway via mitochondrial Bcl-2 family members. Moreover, PD led to the phosphorylation of stresse-activated protein kinases such as JNK and p38, followed by the activation of AP-1. However, pretreatment with SB203580 (a p38 specific inhibitor) suppressed PD-induced p38 and AP-1 activation, and subsequently attenuated the PD-induced apoptosis in AGS cells. These results suggest that p38 activation is responsible for PD-induced apoptosis in AGS cells and PD might be useful for the development as the anticancer agent of gastric cancer. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2mM) and inhibited by compound C (10μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the AMPK-PTEN pathway might be important in the regulation of the inflammatory response in VSMCs.
The importance of the physiological function of phosphatase and tensin homologue (PTEN) is illustrated by its frequent disruption in cancer. By suppressing the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity, PTEN governs a plethora of cellular processes including survival, proliferation, energy metabolism and cellular architecture. Consequently, mechanisms regulating PTEN expression and function, including transcriptional regulation, post-transcriptional regulation by non-coding RNAs, post-translational modifications and protein-protein interactions, are all altered in cancer. The repertoire of PTEN functions has recently been expanded to include phosphatase-independent activities and crucial functions within the nucleus. Our increasing knowledge of PTEN and pathologies in which its function is altered will undoubtedly inform the rational design of novel therapies.
SNX-2112 is an Hsp90 inhibitor which is currently undergoing multiple phase 1 clinical trials; however, its mechanism of action needs to be further elaborated. Here we investigated the effects of SNX-2112 in A-375 cells. SNX-2112 induced the degradation of multiple Hsp90 client proteins, activated both the mitochondrial-mediated and death receptor-mediated apoptotic pathways, downregulated Bcl-2 and Bcl-xL, upregulated Bid, cleaved caspase-9, caspase-7, caspase-3 and PARP, and activated caspase-8. The general caspase inhibitor, z-VAD-fmk, did not completely abolish SNX-2112-induced cell death. SNX-2112 induced autophagy in a time- and dose-dependent manner via Akt/mTOR/p70S6K inhibition. SNX-2112 induces significant apoptosis and autophagy in human melanoma A-375 cells, and may be an effective targeted therapy agent.
Heat shock protein 90 (Hsp90) serves to stabilise and correctly fold multiple significant client proteins associated with cell proliferation and cell survival. However, little is known about the Hsp90 client proteins that regulate cell metabolism. Here, we describe a unique ability of Hsp90 to regulate the stability and activity of AMP-activated kinase (AMPK), a key sensor of cellular energy status. Hsp90 is found to interact with AMPK and to maintain its AMP-activated kinase activity, which in turn is required for the phosphorylation of its substrate, acetyl-CoA carboxylase (ACC), the key enzyme in fatty acid metabolism. Our binding analysis reveals that both the γ subunit and the α subunit of AMPK bind to Hsp90 with a high affinity. We demonstrate that Hsp90 inhibitors, including geldanamycin (GA) and mycoepoxydiene (MED), can induce the dissociation of AMPK from Hsp90, and cause a significant decrease in phosphorylation of AMPK and ACC. Furthermore, we demonstrate that shRNAs of Hsp90 can efficiently suppress the activation of AMPK. These findings not only establish a novel interaction between Hsp90 and AMPK but also suggest a new mechanism for regulating tumour cell fatty acid metabolism.
The AMPK pathway is a metabolic stress-related and energy censor pathway which plays important regulatory roles in normal and malignant cells. This cellular cascade controls generation of signals for initiation of mRNA translation via the mTOR pathway and exhibits regulatory roles on the initiation of autophagy. AMPK activators have been shown to suppress mTOR activity and to negatively control malignant transformation and cell proliferation of diverse malignant cell types. Such properties of AMPK inducers have generated substantial interest for the use of AMPK targeting compounds as antineoplastic agents and have provoked extensive research efforts to better define and classify the mechanisms controlling AMPK activity and its functional consequences in malignant cells.
Insulin resistance is the primary cause responsible for type 2 diabetes. Phosphatase and tensin homolog (PTEN) plays a negative role in insulin signaling and its inhibition improves insulin sensitivity. Metformin is a widely used insulin-sensitizing drug; however, the mechanism by which metformin acts is poorly understood. To gain insight into the role of PTEN, we examined the effect of metformin on PTEN expression. Metformin suppressed the expression of PTEN in an AMP-activated protein kinase (AMPK)-dependent manner in preadipocyte 3T3-L1 cells. Knock-down of PTEN potentiated the increase in insulin-mediated phosphorylation of Akt/ERK. Metformin also increased the phosphorylation of c-Jun N-terminal kinase (JNK)-c-Jun and mammalian target of rapamycin (mTOR)-p70S6 kinase pathways. Both pharmacologic inhibition and knock-down of AMPK blocked metformin-induced phosphorylation of JNK and mTOR. Knock-down of AMPK recovered the metformin-induced PTEN down-regulation, suggesting the involvement of AMPK in PTEN regulation. PTEN promoter activity was suppressed by metformin and inhibition of mTOR and JNK by pharmacologic inhibitors blocked metformin-induced PTEN promoter activity suppression. These findings provide evidence for a novel role of AMPK on PTEN expression and thus suggest a possible mechanism by which metformin may contribute to its beneficial effects on insulin signaling.
Epidemiological evidence suggests a lower incidence of prostate cancer in Asian countries, where soy products are more frequently consumed than in Western countries, indicating that isoflavones from soy have chemopreventive activities in prostate cells. Here, we tested the effects of the soy isoflavone genistein on antioxidant enzymes in DU145 prostate cancer cells. Genistein significantly decreased reactive oxygen species levels and induced the expression of the antioxidant enzymes manganese (Mn) superoxide dismutase (SOD) and catalase, which were associated with AMP-activated protein kinase (AMPK) and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathways. The induced expression of catalase, MnSOD, and PTEN were attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating the effects of genistein primarily depend on AMPK. Furthermore, PTEN is essential for genistein activity, as shown by PTEN transfection in PTEN-deficient PC3 cells. Thus, genistein induces antioxidant enzymes through AMPK activation and increased PTEN expression.
A reduced life span is an outcome associated with many prevalent diseases, including diabetes, obesity, and high blood pressure. In seeking to prevent these diseases, many researchers have looked into potential therapeutic benefits of naturally occurring compounds. AMP-activated protein kinase (AMPK) is a major metabolic-sensing protein implicated in the prevention of metabolic disorders, or in minimizing the effects thereof, via the regulation of both upstream and downstream target molecules. In the field of food and nutrition, the current focus lies in the finding of components that activate AMPK. AMPK is a serine/threonine protein kinase and is activated by several natural compounds, including resveratrol, epigallocatechin gallate, berberine, and quercetin. AMPK activation can induce ATP (adenosine triphosphate) generation through pathways such as glycolysis and beta-oxidation. By contrast, ATP-consuming pathways, including fatty acid and cholesterol syntheses, and gluconeogenesis, are suppressed by AMPK activation. In this review, we will discuss how the activation of AMPK by naturally occurring compounds could help to prevent the development of numerous diseases; the potential mechanism underlying these effects will also be addressed.
AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that has been implicated as a key factor for controlling intracellular lipids and glucose metabolism. Beta-sitosterol, a plant sterol known to prevent cardiovascular disease was identified from Schizonepeta tenuifolia to an AMPK activator. In L6 myotube cells, beta-sitosterol significantly increased phosphorylation of the AMPKalpha subunit and acetyl-CoA carboxylase (ACC) with stimulating glucose uptake. In contrast, beta-sitosterol treatment reduced intracellular levels of triglycerides and cholesterol in L6 cells. These effects were all reversed by pretreatment with AMPK inhibitor Compound C or LKB1 destabilizer radicicol. Similarly, beta-sitosterol-induced phosphorylation of AMPK and ACC was not increased in HeLa cells lacking LKB1. These results together suggest that beta-sitosterol-mediated enhancement of glucose uptake and reduction of triglycerides and cholesterol in L6 cells is predominantly accomplished by LKB1-mediated AMPK activation. Our findings further reveal a molecular mechanism underlying the beneficial effects of beta-sitosterol on glucose and lipid metabolism.
To maintain quality control in cells, mechanisms distinguish among improperly folded peptides, mature and functional proteins, and proteins to be targeted for degradation. The molecular chaperones, including heat-shock protein Hsp90, have the ability to recognize misfolded proteins and assist in their conversion to a functional conformation. Disruption of Hsp90 heterocomplexes by the Hsp90 inhibitor geldanamycin leads to substrate degradation through the ubiquitin-proteasome pathway, implicating this system in protein triage decisions. We previously identified CHIP (carboxyl terminus of Hsc70-interacting protein) to be an interaction partner of Hsc70 (ref. 4). CHIP also interacts directly with a tetratricopeptide repeat acceptor site of Hsp90, incorporating into Hsp90 heterocomplexes and eliciting release of the regulatory cofactor p23. Here we show that CHIP abolishes the steroid-binding activity and transactivation potential of the glucocorticoid receptor, a well-characterized Hsp90 substrate, even though it has little effect on its synthesis. Instead, CHIP induces ubiquitylation of the glucocorticoid receptor and degradation through the proteasome. By remodelling Hsp90 heterocomplexes to favour substrate degradation, CHIP modulates protein triage decisions that regulate the balance between protein folding and degradation for chaperone substrates.
The design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Frequently resistance is intrinsic to the cancer, but as therapy becomes more and more effective, acquired resistance has also become common. The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more energy-dependent transporters that detect and eject anticancer drugs from cells, but other mechanisms of resistance including insensitivity to drug-induced apoptosis and induction of drug-detoxifying mechanisms probably play an important role in acquired anticancer drug resistance. Studies on mechanisms of cancer drug resistance have yielded important information about how to circumvent this resistance to improve cancer chemotherapy and have implications for pharmacokinetics of many commonly used drugs.
Phytosterols (plant sterols) are triterpenes that are important structural components of plant membranes, and free phytosterols serve to stabilize phospholipid bilayers in plant cell membranes just as cholesterol does in animal cell membranes. Most phytosterols contain 28 or 29 carbons and one or two carbon-carbon double bonds, typically one in the sterol nucleus and sometimes a second in the alkyl side chain. Phytostanols are a fully-saturated subgroup of phytosterols (contain no double bonds). Phytostanols occur in trace levels in many plant species and they occur in high levels in tissues of only in a few cereal species. Phytosterols can be converted to phytostanols by chemical hydrogenation. More than 200 different types of phytosterols have been reported in plant species. In addition to the free form, phytosterols occur as four types of "conjugates," in which the 3beta-OH group is esterified to a fatty acid or a hydroxycinnamic acid, or glycosylated with a hexose (usually glucose) or a 6-fatty-acyl hexose. The most popular methods for phytosterol analysis involve hydrolysis of the esters (and sometimes the glycosides) and capillary GLC of the total phytosterols, either in the free form or as TMS or acetylated derivatives. Several alternative methods have been reported for analysis of free phytosterols and intact phytosteryl conjugates. Phytosterols and phytostanols have received much attention in the last five years because of their cholesterol-lowering properties. Early phytosterol-enriched products contained free phytosterols and relatively large dosages were required to significantly lower serum cholesterol. In the last several years two spreads, one containing phytostanyl fatty-acid esters and the other phytosteryl fatty-acid esters, have been commercialized and were shown to significantly lower serum cholesterol at dosages of 1-3 g per day. The popularity of these products has caused the medical and biochemical community to focus much attention on phytosterols and consequently research activity on phytosterols has increased dramatically.
5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers, but its chemo-resistance remains as a major obstacle in clinical settings. In the present study, HT-29 colon cancer cells were markedly sensitized to apoptosis by both 5-FU and genistein compared to the 5-FU treatment alone. There is an emerging evidence that genistein, soy-derived phytoestrogen, may have potential as a chemotherapeutic agent capable of inducing apoptosis or suppressing tumor promoting proteins such as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity of genistein is not known. The present study focused on the correlation of AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK is known as a primary cellular homeostasis regulator and a possible target molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic molecule. Our results demonstrated that the combination of 5-FU and genistein abolished the up-regulated state of COX-2 and prostaglandin secretion caused by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed by the specific activation of AMPK and the up-regulation of p53, p21, and Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU was diminished by the combination treatment with 5-FU and genistein. Furthermore, the reactive oxygen species (ROS) was found as an upstream signal for AMPK activation by genistein. These results suggested that the combination of 5-FU and genistein exert a novel chemotherapeutic effect in colon cancers, and AMPK may be a novel regulatory molecule of COX-2 expression, further implying its involvement in cytotoxicity caused by genistein.
AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.
beta-Sitosterol is the most abundant phytosterol. Phytosterols are enriched in legumes, oil seeds and unrefined plant oils as found in foods such as peanut butter, pistachios and sunflower seeds. beta-Sitosterol inhibits the growth of several specific types of tumor cells in vitro and decreases the size and the extent of tumor metastases in vivo. The effects of beta-sitosterol on the extrinsic apoptotic programmed cell death pathway in human breast MCF-7 and MDA-MB-231 adenocarcinoma cells were examined, along with the extent of its incorporation into cellular membranes and its effects on cell growth, expression of Fas receptor pathway proteins, and caspase-8 activity. The results show that beta-sitosterol exposure promotes its enrichment in transformed cell membranes and significantly inhibits tumor cell growth. Concurrently, Fas levels and caspase-8 activity are significantly increased. These actions are specific, as expression of other proteins of the Fas receptor pathway, including Fas ligand, FADD, p-FADD and caspase-8, remain unchanged. These findings support the hypothesis that beta-sitosterol is an effective apoptosis-promoting agent and that incorporation of more phytosterols in the diet may serve a preventive measure for breast cancer.
PTEN inhibits cell proliferation, promotes cells apoptosis, and induces cell cycle arrest via downregulating the PI3K/AKT/hTERT in lung adenocarcinoma A549 cells
- Lu
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
- Engelman
Numair, Chemopreventive potential of beta-sitosterol in experimental colon cancer model—an in vitro and in vivo study
- Basker
Sayeed, and S.S. Ameen, Beta-sitosterol: a promising but orphan nutraceutical to fight against cancer
- Bin
Reactive oxygen species-mediated activation of AMP-activated protein kinase and c-Jun N-terminal kinase plays a critical role in beta-sitosterol-induced apoptosis in multiple myeloma U226 cells
- Sook