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Exploring the Therapeutic Potential of Traditional Medicinal Foods in Cancer Treatment: Molecular Evidence and Bioactivities
Abstract
Traditional medicinal foods derived from natural sources have gained increasing attention in recent years due to their perceived health benefits and potential therapeutic properties and are deeply rooted in cultural practices. This review aimed at understanding their potential health benefits, emphasizes the need to identify the key bioactive substances in traditional home medicine. We have discussed the bioactive properties, molecular targets, and anti-cancer effects of various compounds such as curcumin, genistein, berberine, resveratrol, and, quercetin present in traditional medicinal foods. Our study highlights the potential of traditional medicinal food in the prevention and management of various health conditions, including cardiovascular diseases, cancer and neurodegenerative disorders as evident from in vitro, in vivo and clinical trials. Additionally, our study explores the mechanistic action of various bioactive constituents of grapes, rosemary, barberry, turmeric and garlic that have been shown to interfere with cancer growth, proliferation, metastasis, angiogenesis, and induce apoptosis by targeting various pathways and the cell cycle. Additionally, a wide range of healing abilities of medicinal foods including their impact on cancer cells demonstrate their direct anti-tumor potential along with antioxidant and antiinflammatory properties. To summarize, the present review highlights that integrating the insights of contemporary science with the age-old wisdom of traditional medicine in a systematic way holds immense potential for developing alternate and effective approaches to cancer therapeutics and offering evidence-based dietary recommendations.
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Resveratrol is a pleiotropic phytochemical belonging to the stilbene family. Though it is only significantly present in grape products, a huge amount of preclinical studies investigated its anticancer properties in a plethora of cellular and animal models. Molecular mechanisms of resveratrol involved signaling pathways related to extracellular growth factors and receptor tyrosine kinases; formation of multiprotein complexes and cell metabolism; cell proliferation and genome instability; cytoplasmic tyrosine kinase signaling (cytokine, integrin, and developmental pathways); signal transduction by the transforming growth factor-β super-family; apoptosis and inflammation; and immune surveillance and hormone signaling. Resveratrol also showed a promising role to counteract multidrug resistance: in adjuvant therapy, associated with 5-fluoruracyl and cisplatin, resveratrol had additive and/or synergistic effects increasing the chemosensitization of cancer cells. Resveratrol, by acting on diverse mechanisms simultaneously, has been emphasized as a promising, multi-target, anticancer agent, relevant in both cancer prevention and treatment.
The differentiation, survival, and effector function of tumor-specific CD8⁺ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies.
Vinca alkaloids including vincristine, vinblastine, vindesine, and vinflunine are chemotherapeutic compounds commonly used to treat various cancers. Vinca alkaloids are one of the first microtubule-targeting agents to be produced and certified for the treatment of hematological and lymphatic neoplasms. Microtubule targeting agents like vincristine and vinblastine work by disrupting microtubule dynamics, causing mitotic arrest and cell death. The key issues facing vinca alkaloids applications include establishing an environment-friendly production technique based on microorganisms, as well as increasing bioavail-ability without causing harm to patient's health. The low yield of these vinca alkaloids from the plant and the difficulty of meeting their huge colossal demand around the globe prompted researchers to create a variety of approaches. Endophytes could thus be selected to produce beneficial secondary metabolites required for the biosynthesis of vinca alkaloids. This review covers the significant aspects of these vital drugs, from their discovery to the present day, in a concise manner. In addition , we emphasize the major hurdles that must be overcome in the coming years to improve vinca alkaloid's effectiveness.
Carbon-based nanostructures are attracting a lot of attention because of their very low toxicity, excellent visible light-triggered optical and photothermal properties, and intriguing applications. Currently, the development of multifunctional carbon-based nanostructures for a synergistic chemo-photothermal approach is a challenging topic for the advancement of cancer treatment. Here, we report an unprecedented example of photoresponsive carbon-based polymer dots (CPDs-PNM) obtained by a one-pot thermal process from poly(N-isopropylacrylamide) (PNIPAM) without using organic solvent and additional reagents. The CPDs-PNM nanostructures were characterized by spectroscopic techniques, transmission electron microscopy, and atomic force microscopy. The CPDs-PNM exhibited high photothermal conversion efficiency, lower critical solution temperature (LCST) behavior, and good cytarabine (arabinosyl cytosine, AraC) loading capacity (62.3%). The formation of a CPDs-PNM/AraC adduct and photothermal-controlled drug release, triggered by green light excitation, were demonstrated by spectroscopic techniques, and the drug-polymer interaction and drug release mechanism were well supported by modeling simulation calculations. The cellular uptake of empty and AraC-loaded CPDs-PNM was imaged by confocal laser scanning microscopy. In vitro experiments evidenced that CPDs-PNM did not affect the viability of neuroblastoma cells, while the CPDs-PNM/AraC adduct under light irradiation exhibited significantly higher toxicity than AraC alone by a combined chemo-photothermal effect.
Silymarin, a milk thistle extract, has anti-inflammatory, immunomodulatory, anti-lipid peroxidative, anti-fibrotic, anti-oxidative, and anti-proliferative properties. Silymarin exhibits not only anti-cancer functions through modulating various hallmarks of cancer, including cell cycle, metastasis, angiogenesis, apoptosis, and autophagy, by targeting a plethora of molecules, but also plays protective roles against chemotherapy-induced toxicity, such as nephrotoxicity, hepatotoxicity, cardiotoxicity, and neurotoxicity. One of the problems of silymarin in (pre)clinical studies is its poor water solubility, leading to low intestinal absorption and, therefore, low bioavailability. To address these challenges, silymarin nanoformulations have emerged with added benefits, including excellent drug loading, sustained release, improved cellular uptake, and targeting tumor cells. Besides the chemical and biological properties, here we summarized the anti-cancer functions and the mechanism of action of silymarin in both free form and nanoformulations and its protective roles against chemotherapy-induced toxicity.
Cancer is one of the deadliest non communicable diseases. Numerous anticancer medications have been developed to target the molecular pathways driving cancer. However, there has been no discernible increase in the overall survival rate in cancer patients. Therefore, innovative chemo-preventive techniques and agents are required to supplement standard cancer treatments and boost their efficacy. Fruits and vegetables should be tapped into as a source of compounds that can serve as cancer therapy. Phytochemicals play an important role as sources of new medication in cancer treatment. Some synthetic and natural chemicals are effective for cancer chemoprevention, i.e., the use of exogenous medicine to inhibit or impede tumor development. They help regulate molecular pathways linked to the development and spread of cancer. They can enhance antioxidant status, inactivating carcinogens, suppressing proliferation, inducing cell cycle arrest and death, and regulating the immune system. While focusing on four main categories of plant-based anticancer agents, i.e., epipodophyllotoxin, camptothecin derivatives, taxane diterpenoids, and vinca alkaloids and their mode of action, we review the anticancer effects of phytochemicals, like quercetin, curcumin, piperine, epigallocatechin gallate (EGCG), and gingerol. We examine the different signaling pathways associated with cancer and how inflammation as a key mechanism is linked to cancer growth.
Natural products have been an invaluable and useful source of anticancer agents over the years. Several compounds have been synthesized from natural products by modifying their structures or by using naturally occurring compounds as building blocks in the synthesis of these compounds for various purposes in different fields, such as biology, medicine, and engineering. Multiple modern and costly treatments have been applied to combat cancer and limit its lethality, but the results are not significantly refreshing. Natural products, which are a significant source of new therapeutic drugs, are currently being investigated as potential cytotoxic agents and have shown a positive trend in preclinical research and have prompted numerous innovative strategies in order to combat cancer and expedite the clinical research. Natural products are becoming increasingly important for drug discovery due to their high molecular diversity and novel biofunctionality. Furthermore, natural products can provide superior efficacy and safety due to their unique molecular properties. The objective of the current review is to provide an overview of the emergence of natural products for the treatment and prevention of cancer, such as chemosensitizers, immunotherapeutics, combinatorial therapies with other anticancer drugs, novel formulations of natural products, and the molecular mechanisms underlying their anticancer properties.
Polyphenon E (Poly E) is a standardized, caffeine-free green tea extract with defined polyphenol content. Poly E is reported to confer chemoprotective activity against prostate cancer (PCa) progression in the TRAMP model of human PCa, and has shown limited activity against human PCa in human trials. The molecular mechanisms of the observed Poly E chemopreventive activity against PCa are not fully understood. We hypothesized that Poly E treatment of PCa cells induces gene expression changes, which could underpin the molecular mechanisms of the limited Poly E chemoprevention activity against PCa. PC-3 cells were cultured in complete growth media supplemented with varied Poly E concentrations for 24 h, then RNA was isolated for comparative DNA microarray (0 vs. 200 mg/L Poly E) and subsequent TaqMan qRT-PCR analyses. Microarray data for 54,613 genes were filtered for >2-fold expression level changes, with 8319 genes increased and 6176 genes decreased. Eight genes involved in key signaling or regulatory pathways were selected for qRT-PCR. Two genes increased expression significantly, MXD1 (13.98-fold; p = 0.0003) and RGS4 (21.98-fold; p = 0.0011), by qRT-PCR. MXD1 and RGS4 significantly increased gene expression in Poly E-treated PC-3 cells, and the MXD1 gene expression increases were Poly E dose-dependent.
Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype–phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype–phenotype association data is needed to enable the clinical use of sequencing data.
Withaferin A is a C28 steroidal lactone derived from the plant Withania somnifera, commonly known as Ashwagandha. Withaferin A has received great attention for its anticancer properties noted in cancer cells of various origins. Extracts of Withania somnifera have been used in traditional Ayurvedic and Unani Indian medicine for their various pharmacological benefits. In recent years, Withania somnifera or Ashwagandha extract has become popularized as a health supplement marketed for its stress and anxiety reducing effects. Withaferin A is one of the most studied withanolides extracted from Withania somnifera that has gained great attention for its anticancer, anti-inflammatory, metabolic, and pro-apoptotic effects. Extensive in vivo and in vitro studies have depicted Withaferin A’s interactions with key role players in cancerous activity of the cell to exert its pro-apoptotic effects. Withaferin A interactions with NF-κB, STAT, Hsp90, ER-α, p53, and TGF-β have noted inhibition in cancer cell proliferation and cell cycle arrest in G2/M stage, ultimately leading to apoptosis or cell death. This review highlights pro-apoptotic properties of Withaferin A including generation of reactive oxidative species, Par-4 activation, endoplasmic reticulum stress (ER) induction, and p53 activation. Analysis of Withaferin A’s involvement in various oncogenic pathways leading to malignant neoplasm and its pharmacologic activity in conjunction with various cancer drugs provides promising evidence in therapeutic potential of Withaferin A as a cancer treatment.
We recently reported that carnosol induces ROS-dependent autophagy and apoptosis in breast cancer cells. We also reported that carnosol inhibits breast cancer cell migration, invasion, and in ovo tumor growth, as well as targets STAT3, PCAF, and p300 to proteasome degradation. Here, we investigated the molecular mechanisms underlying its anti-malignant activity in breast cancer. We report that carnosol induces a ROS-dependent type I and type II programmed cell death (PCD-I or PCD-II, respectively), which occurred independently of each other. Indeed, chemical inhibition of autophagy had no effect on the induction of apoptosis, evident by the absence of cleaved PARP. Electron microscopy revealed that carnosol-treated cells exhibited enlarged endoplasmic reticulum, characteristic of ER stress. Markers of the three unfolded protein response pathways (PERK, IRE-1 α, and ATF6), namely ATF4, CHOP, phospho-IRE-1α, XBP1S, and cleaved ATF6 were upregulated in a ROS-dependent manner. In addition, carnosol induced a ROS-dependent activation of p38MAPK, increased the overall level of protein polyubiquitination, and targeted mTOR protein to proteasome degradation. Interestingly, inhibition of p38MAPK, by SB202190 and 203580, reduced cell death, selectively blocked the induction of IRE-1α and ATF6 UPR sensors and inhibited autophagy. In addition, inhibition of p38 reduced the carnosol-induced polyubiquitination and rescued mTOR, PCAF, and STAT3 from proteasomal degradation. Importantly, activation of PERK sensors and induction of apoptosis occurred independently of p38 activation. Taken together, our results suggest that ROS-dependent induced-ER stress contributes to carnosol-induced apoptotic and autophagic cell death in breast cancer cells, and further confirm that carnosol is a promising agent for breast cancer therapy.
Breast cancer (BC) is one of the most common malignancies in women. Although widespread successful synthetic drugs are available, natural compounds can also be considered as significant anticancer agents for treating BC. Some natural compounds have similar effects as synthetic drugs with fewer side effects on normal cells. Therefore, we aimed to unravel and analyze several molecular mechanisms of genistein (GNT) against BC. GNT is a type of dietary phytoestrogen included in the flavonoid group with a similar structure to estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutic drugs. Previous research reported that GNT could target the estrogen receptor (ER) human epidermal growth factor receptor-2 (HER2) and several signaling molecules against multiple BC cell lines and sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. More specifically, GNT mediates the anticancer mechanism through apoptosis induction, arresting the cell cycle, inhibiting angiogenesis and metastasis, mammosphere formation, and targeting and suppressing tumor growth factors. Furthermore, it acts via upregulating tumor suppressor genes and downregulating oncogenes in vitro and animal model studies. In addition, this phytochemical synergistically reverses the resistance mechanism of standard chemotherapeutic drugs, increasing their efficacy against BC. Overall, in this review, we discuss several molecular interactions of GNT with numerous cellular targets in the BC model and show its anticancer activities alone and synergistically. We conclude that GNT can have favorable therapeutic advantages when standard drugs are not available in the pharma markets.
The flavonoid silymarin extracted from the seeds of Sylibum marianum is a mixture of 6 flavolignan isomers. The 3 more important isomers are silybin (or silibinin), silydianin, and silychristin. Silybin is functionally the most active of these compounds. This group of flavonoids has been extensively studied and they have been used as hepato-protective substances for the mushroom Amanita phalloides intoxication and mainly chronic liver diseases such as alcoholic cirrhosis and nonalcoholic fatty liver. Hepatitis C progression is not, or slightly, modified by silymarin. Recently, it has also been proposed for SARS COVID-19 infection therapy. The biochemical and molecular mechanisms of action of these substances in cancer are subjects of ongoing research. Paradoxically, many of its identified actions such as antioxidant, promoter of ribosomal synthesis, and mitochondrial membrane stabilization, may seem protumoral at first sight, however, silymarin compounds have clear anticancer effects. Some of them are: decreasing migration through multiple targeting, decreasing hypoxia inducible factor-1α expression, inducing apoptosis in some malignant cells, and inhibiting promitotic signaling among others. Interestingly, the antitumoral activity of silymarin compounds is limited to malignant cells while the nonmalignant cells seem not to be affected. Furthermore, there is a long history of silymarin use in human diseases without toxicity after prolonged administration. The ample distribution and easy accessibility to milk thistle-the source of silymarin compounds, its over the counter availability, the fact that it is a weed, some controversial issues regarding bioavailability, and being a nutraceutical rather than a drug, has somehow led medical professionals to view its anticancer effects with skepticism. This is a fundamental reason why it never achieved bedside status in cancer treatment. However, in spite of all the antitumoral effects, silymarin actually has dual effects and in some cases such as pancreatic cancer it can promote stemness. This review deals with recent investigations to elucidate the molecular actions of this flavonoid in cancer, and to consider the possibility of repurposing it. Particular attention is dedicated to silymarin's dual role in cancer and to some controversies of its real effectiveness.
Cancer is a leading cause of morbidity and mortality around the globe. Reactive oxygen species (ROS) play contradicting roles in cancer incidence and progression. Antioxidants have attracted attention as emerging therapeutic agents. Among these are flavonoids, which are natural polyphenols with established anticancer and antioxidant capacities. Increasing evidence shows that flavonoids can inhibit carcinogenesis via suppressing ROS levels. Surprisingly, flavonoids can also trigger excessive oxidative stress, but this can also induce death of malignant cells. In this review, we explore the inherent characteristics that contribute to the antioxidant capacity of flavonoids, and we dissect the scenarios in which they play the contrasting role as pro-oxidants. Furthermore, we elaborate on the pathways that link flavonoid-mediated modulation of ROS to the prevention and treatment of cancer. Special attention is given to the ROS-mediated anticancer functions that (-)-epigallocatechin gallate (EGCG), hesperetin, naringenin, quercetin, luteolin, and apigenin evoke in various cancers. We also delve into the structure-function relations that make flavonoids potent antioxidants. This review provides a detailed perspective that can be utilized in future experiments or trials that aim at utilizing flavonoids or verifying their efficacy for developing new pharmacologic agents. We support the argument that flavonoids are attractive candidates for cancer therapy.
The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NFκB signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.
Cancer is a condition where the body cells multiply in an uncontrollable manner. Chemoprevention of cancer is a broad term that describes the involvement of external agents to slow down or suppress cancer growth. Synthetic and natural compounds are found useful in cancer chemoprevention. The occurrence of global cancer type varies, depending on many factors such as environmental, lifestyle, genetic etc. Cancer is often preventable in developed countries with advanced treatment modalities, whereas it is a painful death sentence in developing and low-income countries due to the lack of modern therapies and awareness. One best practice to identify cancer control measures is to study the origin and risk factors associated with common types. Based on these factors and the health status of patients, stage, and severity of cancer, type of treatment is decided. Even though there are well-established therapies, cancer still stands as one of the major causes of death and a public health burden globally. Research shows that most cancers can be prevented, treated, or the incidence can be delayed. Phytochemicals from various medicinal plants were reported to reduce various risk factors associated with different types of cancer through their chemopreventive role. This review highlights the role of bioactive compounds or natural products from plants in the chemoprevention of cancer. There are many plant based dietary factors involved in the chemoprevention process. The review discusses the process of carcinogenesis and chemoprevention using plants and phytocompounds, with special reference to five major chemopreventive phytocompounds. The article also summarizes the important chemopreventive mechanisms and signaling molecules involved in the process. Since the role of antioxidants in chemoprevention is inevitable, an insight into plant-based antioxidant compounds that fight against this dreadful disease at various stages of carcinogenesis and disease progression is discussed. This will fill the research gap in search of chemopreventive natural compounds and encourage scientists in clinical trials of anticancer agents from plants.
Antibiotic resistance or microbial drug resistance is emerging as a serious threat to human healthcare globally, and the multidrug-resistant (MDR) strains are imposing major hurdles to the progression of drug discovery programs. Newer antibiotic-resistance mechanisms in microbes contribute to the inefficacy of the existing drugs along with the prolonged illness and escalating expenditures. The injudicious usage of the conventional and commonly available antibiotics in human health, hygiene, veterinary and agricultural practices is proving to be a major driver for evolution, persistence and spread of antibiotic-resistance at a frightening rate. The drying pipeline of new and potent antibiotics is adding to the severity. Therefore, novel and effective new drugs and innovative therapies to treat MDR infections are urgently needed. Apart from the different natural and synthetic drugs being tested, plant secondary metabolites or phytochemicals are proving efficient in combating the drug-resistant strains. Various phytochemicals from classes including alkaloids, phenols, coumarins, terpenes have been successfully demonstrated their inhibitory potential against the drug-resistant pathogens. Several phytochemicals have proved effective against the molecular determinants responsible for attaining the drug resistance in pathogens like membrane proteins, biofilms, efflux pumps and bacterial cell communications. However, translational success rate needs to be improved, but the trends are encouraging. This review highlights current knowledge and developments associated challenges and future prospects for the successful application of phytochemicals in combating antibiotic resistance and the resistant microbial pathogens.
Many anticancer active compounds are known to have the capacity to destroy pathologically proliferating cancer cells in the body, as well as to destroy rapidly proliferating normal cells. Despite remarkable advances in cancer research over the past few decades, the inclusion of natural compounds in researches as potential drug candidates is becoming increasingly important. However, the perception that the natural is reliable is an issue that needs to be clarified. Among the various chemical classes of natural products, anthraquinones have many biological activities and have also been proven to exhibit a unique anticancer activity. Emodin, an anthraquinone derivative, is a natural compound found in the roots and rhizomes of many plants. The anticancer property of emodin, a broad-spectrum inhibitory agent of cancer cells, has been detailed in many biological pathways. In cancer cells, these molecular mechanisms consist of suppressing cell growth and proliferation through the attenuation of oncogenic growth signaling, such as protein kinase B (AKT), mitogen-activated protein kinase (MAPK), HER-2 tyrosine kinase, Wnt/-catenin, and phosphatidylinositol 3-kinase (PI3K). However, it is known that emodin, which shows toxicity to cancer cells, may cause kidney toxicity, hepatotoxicity, and reproductive toxicity especially at high doses and long-term use. At the same time, studies of emodin, which has poor oral bioavailability, to transform this disadvantage into an advantage with nano-carrier systems reveal that natural compounds are not always directly usable compounds. Consequently, this review aimed to shed light on the anti-proliferative and anti-carcinogenic properties of emodin, as well as its potential toxicities and the advantages of drug delivery systems on bioavailability.
Bioactive plant derived compounds are important for a wide range of therapeutic applications, and some display promising anticancer properties. Further evidence suggests that phytochemicals modulate autophagy and apoptosis, the two crucial cellular pathways involved in the underlying pathobiology of cancer development and regulation. Pharmacological targeting of autophagy and apoptosis signaling using phytochemicals therefore offers a promising strategy that is complementary to conventional cancer chemotherapy. In this review, we sought to highlight the molecular basis of the autophagic-apoptotic pathway to understand its implication in the pathobiology of cancer, and explore this fundamental cellular process as a druggable anticancer target. We also aimed to present recent advances and address the limitations faced in the therapeutic development of phytochemical-based anticancer drugs.
Ovarian cancer remains the deadliest of all gynecologic malignancies. Our expanding knowledge of ovarian cancer immunology has allowed the development of therapies that generate systemic anti-tumor immune responses. Current immunotherapeutic strategies include immune checkpoint blockade, cellular therapies, and cancer vaccines. Vaccine-based therapies are designed to induce both adaptive and innate immune responses directed against ovarian cancer associated antigens. Tumor-specific effector cells, in particular cytotoxic T cells, are activated to recognize and eliminate ovarian cancer cells. Vaccines for ovarian cancer have been studied in various clinical trials over the last three decades. Despite evidence of vaccine-induced humoral and cellular immune responses, the majority of vaccines have not shown significant anti-tumor efficacy. Recently, improved vaccine development using dendritic cells or synthetic platforms for antigen presentation have shown promising clinical benefits in patients with ovarian cancer. In this review, we provide an overview of therapeutic vaccine development in ovarian cancer, discuss proposed mechanisms of action, and summarize the current clinical experience.
The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure–activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure–activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.
A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French–American–British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
Our previous studies demonstrated that the natural compound emodin blocks the tumor-promoting feedforward interactions between cancer cells and macrophages, and thus ameliorates the immunosuppressive state of the tumor microenvironment. Since tumor-associated macrophages (TAMs) also affect epithelial mesenchymal-transition (EMT) and cancer stem cell (CSC) formation, here we aimed to test if emodin as a neoadjuvant therapy halts breast cancer metastasis by attenuating TAM-induced EMT and CSC formation of breast cancer cells.
Methods: Bioinformatical analysis was performed to examine the correlation between macrophage abundance and EMT/CSC markers in human breast tumors. Cell culture and co-culture studies were performed to test if emodin suppresses TGF-β1 or macrophage-induced EMT and CSC formation of breast cancer cells, and if it inhibits breast cancer cell migration and invasion. Using mouse models, we tested if short-term administration of emodin before surgical removal of breast tumors halts breast cancer post-surgery metastatic recurrence in the lungs. The effects of emodin on TGF-β1 signaling pathways in breast cancer cells were examined by western blots and immunofluorescent imaging.
Results: Macrophage abundance positively correlates with EMT and CSC markers in human breast tumors. Emodin suppressed TGF-β1 production in breast cancer cells and macrophages and attenuated TGF-β1 or macrophage-induced EMT and CSC formation of breast cancer cells. Short-term administration of emodin before surgery halted breast cancer post-surgery metastatic recurrence in the lungs by reducing tumor-promoting macrophages and suppressing EMT and CSC formation in the primary tumors. Mechanistic studies revealed that emodin inhibited both canonical and noncanonical TGF-β1 signaling pathways in breast cancer cells and suppressed transcription factors key to EMT and CSC.
Conclusion: Natural compound emodin suppresses EMT and CSC formation of breast cancer cells by blocking TGF-β1-mediated crosstalk between TAMs and breast cancer cells. Our study provides evidence suggesting that emodin harbors the potential for clinical development as a new effective and safe agent to halt metastatic recurrence of breast cancer.
Studying prostate cancer is important due to its high annual incidences and mortality rates in the world. Although prostate cancer mortality rates are reduced using new therapy, complicated routes and side effects of these current drugs require a daily available treatment for prevention. Lycopene is a natural, prominent, and effective product which has a high value in diet. The anti-cancer effect, non-toxicity, safety and preventive or therapeutic roles of lycopene have been investigated in several studies. In the current review, we have collected information about the anti-cancer, anti-progressive and apoptotic effects of lycopene on prostate cancer. This article is a summary of the most important original and review articles on lycopene and its anticancer effects that are systematically categorized and presents information about the molecular structure, different sources, biological functions, and its in-vivo and in-vitro effects of lycopene on variety of cancerous and normal cells. The clinical studies provide a clear image for continuous use of this adjunctive dietary for different type of cancers, especially prostate cancer in men. In addition, this article discusses the various molecular pathways activated by lycopene that eventually prevent or suppress cancer. Lycopene has been found to effectively suppress the progression and proliferation, arrest in-cell cycle, and induce apoptosis of prostate cancer cells in both in-vivo and in-vitro conditions. Additionally, lycopene showed that it could modulate the signaling pathways and their protein for the treatment or prevention of prostate cancer.
Black pepper (Piper nigrum L.) has been employed in medicine (epilepsy, headaches, and diabetes), where its effects are mainly attributed to a nitrogen alkaloid called piperidine (1-(1-[1,3-benzodioxol-5-yl]-1-oxo-2,4 pentenyl) piperidine). Piperine co-administered with vitamins and minerals has improved its absorption. Therefore, this study aimed to describe the impact of the joint administration of iron (Fe) plus black pepper in physically active healthy individuals. Fe is a micronutrient that aids athletic performance by influencing the physiological functions involved in endurance sports by improving the transport, storage, and utilization of oxygen. Consequently, athletes have risk factors for Fe depletion, Fe deficiency, and eventually, anemia, mainly from mechanical hemolysis, gastrointestinal disturbances, and loss of Fe through excessive sweating. Declines in Fe stores have been reported to negatively alter physical capacities such as aerobic capacity, strength, and skeletal muscle recovery in elite athletes. Thus, there is a need to maintain Fe storage, even if Fe intake meets the recommended daily allowance (RDA), and Fe supplementation may be justified in physically active individuals, in states of Fe deficiency, with or without anemia. Females, in particular, should monitor their Fe hematological profile. The recommended oral Fe supplements are ferrous or ferric salts, sulfate, fumarate, and gluconate. These preparations constitute the first line of treatment; however, the high doses administered have gastrointestinal side effects that reduce tolerance and adherence to treatment. Thus, a strategy to counteract these adverse effects is to improve the bioavailability of Fe. Therefore, piperine may benefit the absorption of Fe through its bioavailability enhancement properties. Three research studies of Fe associated with black pepper have reported improvements in parameters related to the metabolism of Fe, without adverse effects. Although more research is needed, this could represent an advance in oral Fe supplementation for physically active individuals.
Background:
According to the Independent High-level Commission on Non-communicable Diseases (NCD) of the World Health Organization (WHO), global reduction in lung cancer mortality has been achieved since the year 2000, although this effect is not sufficient to reach the 30% reduction of mortality from NCDs by the year 2030, as stipulated by the United Nations Sustainable Development Goal 3.4. The objective of this study was to analyze whether the lifestyle changes implemented by the WHO at country level could have an impact on mortality from this form of cancer.
Methods:
WHO statistics, based on the unified mortality and causes-of-death reports of Member-State countries, were used to evaluate global lung cancer mortality trends and make comparisons and assessments of different types of community-based, country-wide interventions.
Results:
The lung cancer mortality decline was associated with the anti-tobacco campaign initiated by the WHO in the last 15 to 20 years. Comprehensive tobacco control remained the major and most successful lifestyle modification measure. In countries with declining lung cancer mortality, 91% of countries had decreasing tobacco prevalence in males and 82% in females. Country- wide measures to increase physical activity had a strong tendency to be better implemented in countries with declining lung cancer mortality (t = 1.79, P > 0.05). Other WHO "best-buy" lifestyle modification campaigns (diet and alcohol) had been carried out for shorter periods, and their associations with lung cancer were less strong than tobacco. There was no significant difference between countries with declining and increasing lung cancer mortality in the measures for reduction of harmful alcohol use (t = 0.92, P > 0.05) and unhealthy diet reduction measures (t = 0.84, P > 0.05).
Conclusion:
Following WHO "best-buys" should facilitate to move countries towards the NCD including lung cancer mortality reduction targets. Governments and communities must embrace these targets with coordinated effective action for better health.
Antimicrobial peptides (AMPs), or host defense peptides, are small cationic or amphipathic molecules produced by prokaryotic and eukaryotic organisms that play a key role in the innate immune defense against viruses, bacteria and fungi. AMPs have either antimicrobial or anticancer activities. Indeed, cationic AMPs are able to disrupt microbial cell membranes by interacting with negatively charged phospholipids. Moreover, several peptides are capable to trigger cytotoxicity of human cancer cells by binding to negatively charged phosphatidylserine moieties which are selectively exposed on the outer surface of cancer cell plasma membranes. In addition, some AMPs, such as LTX-315, have shown to induce release of tumor antigens and potent damage associated molecular patterns by causing alterations in the intracellular organelles of cancer cells. Given the recognized medical need of novel anticancer drugs, AMPs could represent a potential source of effective therapeutic agents, either alone or in combination with other small molecules, in oncology. In this review we summarize and describe the properties and the mode of action of AMPs as well as the strategies to increase their selectivity toward specific cancer cells.
The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as “omics” approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.
Cancer is the second leading cause of death in the US. Current major treatments for cancer management include surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy and immunotherapy. Despite the endeavors and achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies. Drug resistance, either existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most relapses of cancer, one of the major causes of death of the disease. Heterogeneity among patients and tumors, and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with. Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes. In this review, intrinsic and acquired resistance will be discussed. In addition, new discoveries in mechanisms of drug resistance will be reviewed. Particularly, we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment. The complexity of drug resistance development suggests that combinational and personalized therapies, which should take ATP into consideration, might provide better strategies and improved efficacy for fighting drug resistance in cancer.
Taxane‐derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nab‐paclitaxel. Taxane treatment is associated with neurotoxicity, a well‐known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose‐limiting side effect of taxanes, affecting up to 97% of paclitaxel‐treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane‐induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long‐term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxane‐induced neurotoxicity when they are used therapeutically. This article provides an up‐to‐date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect.
Oral squamous cell carcinoma is the sixth most common type of cancer globally, which is associated with high rates of cancer-related deaths. Metastasis to distant organs is the main reason behind worst prognostic outcome of oral cancer. In the present study, we aimed at evaluating the effects of a natural plant flavonoid, luteolin-7-O-glucoside, on oral cancer cell migration and invasion. The study findings showed that in addition to preventing cell proliferation, luteolin-7-O-glucoside caused a significant reduction in oral cancer cell migration and invasion. Mechanistically, luteolin-7-O-glucoside caused a reduction in cancer metastasis by reducing p38 phosphorylation and downregulating matrix metalloproteinase (MMP)-2 expression. Using a p38 inhibitor, SB203580, we proved that luteolin-7-O-glucoside exerts anti-migratory effects by suppressing p38-mediated increased expression of MMP-2. This is the first study to demonstrate the luteolin-7-O-glucoside inhibits cell migration and invasion by regulating MMP-2 expression and extracellular signal-regulated kinase pathway in human oral cancer cell. The study identifies luteolin-7-O-glucoside as a potential anti-cancer candidate that can be utilized clinically for improving oral cancer prognosis.
Cancer and other diseases can be treated with cubosomes, which are lyotropic nonlamellar liquid crystalline nanoparticles (LCNs). These cubosomes can potentially be a highly versatile carrier with theranostic efficacy, as they can be ingested, applied topically, or injected intravenously. Recent years have seen substantial progress in the synthesis, characterization, regulation of drug release patterns, and target selectivity of loaded anticancer bioactive compounds. However, its use in clinical settings has been slow and necessitates additional proof. Recent progress and roadblocks in using cubosomes as a nanotechnological intervention against various cancers are highlighted. In the last few decades, advances in biomedical nanotechnology have allowed for the development of "smart" drug delivery devices that can adapt to external stimuli. By improving therapeutic targeting efficacy and lowering the negative effects of payloads, these well-defined nanoplatforms can potentially promote patient compliance in response to specific stimuli. Liposomes and niosomes, two other well-known vesicular systems, share a lipid basis with cubosomes. Possible applications include a novel medication delivery system for hydrophilic, lipophilic, and amphiphilic drugs. We evaluate the literature on cubosomes, emphasizing their potential use in tumor-targeted drug delivery applications and critiquing existing explanations for cubosome self-assembly, composition, and production. As cubosome dispersion has bioadhesive and compatible features, numerous drug delivery applications, including oral, ocular, and transdermal, are also discussed in this review.
The tremendous success of immunotherapy in clinical trials has led to its establishment as a new pillar of cancer therapy. However, little clinical efficacy has been achieved in microsatellite stable colorectal cancer (MSS-CRC), which constitutes most CRC tumors. Here, we discuss the molecular and genetic heterogeneity of CRC. We review the immune escape mechanisms, and focus on the latest advances in immunotherapy as a treatment modality for CRC. By providing a better understanding of the tumor microenvironment (TME) and the molecular mechanisms underlying immunoevasion, this review offers an insight into developing therapeutic strategies that are effective for patients with various subsets of CRC.
Purpose:
Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone.
Patients and methods:
Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days.
Results:
A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm.
Conclusion:
Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.
Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays. In addition, we aimed to identify novel biomolecules that may be involved in the mechanism of action of IM using RNA sequencing, western blotting, and inhibition assays. The IC50 values after 72 h of exposure to IM and SN-38, drugs to which the Panc-1 cells are most sensitive among the tested anticancer agents, were 43.1 ± 16.8 nM and 165 ± 37 nM, respectively. IM showed a cytostatic effect equal to or greater than that of the clinically used pancreatic cancer therapeutic drugs. RNA sequencing and protein expression analysis revealed that expression of stimulator of interferon genes (STING) increased at low IM concentration, whereas cell viability decreased. Co-exposure of IM and STING inhibitor, H-151, to Panc-1 or MIA PaCa-2 cell lines canceled the growth-inhibitory effects of IM alone. In conclusion, IM may have an efficacy comparable to that of existing pancreatic cancer therapeutic agents on the less drug-sensitive Panc-1 cell line and the immune-related molecule STING plays a role in the mechanism of action of IM.
Ellagic acid (EA), found in fruits and foods, has been shown to be effective in the treatment of breast, colon and bladder cancer. However, due to the complexity of colon cancer, the therapeutic mechanism of EA for colon cancer is still unclear. Cell Counting Kit-8 (CCK-8) assay were employed to investigate the cell proliferation. Western blotting and flow cytometry assays were utilized to investigate apoptosis and autophagy in CRC cells (HCT116), respectively. Moreover, western blotting and luciferase reporter assays were evaluated the effect of EA on AMPK/mTOR pathway. Through flow cytometry analysis, EA could promote the apoptosis of HCT116 cells. In addition, EA can reduce the phosphorylation of mTOR, promoted phosphorylation of AMPK, and induced autophagy in HCT116 cells. Also, Dorsomorphin pretreatment can reduce the expression of autophagy protein, which indicates that EA induces autophagy through AMPK/mTOR pathway. These results suggest that EA inhibits the growth of colon cancer through AMPK/mTOR pathway and induces apoptosis and protective autophagy.
The use of plant secondary metabolites has gained considerable attention among clinicians in the prevention and treatment of cancer. A secondary metabolite isolated mainly from the roots and rhizomes of Podophyllum species (Berberidaceae) is aryltetralin lignan - podophyllotoxin (PTOX). The purpose of this review is to discuss the therapeutic properties of PTOX as an important anticancer compound of natural origin. The relevant information regarding the antitumor mechanisms of podophyllotoxin and its derivatives were collected and analyzed from scientific databases. The results of the analysis showed PTOX exhibits potent cytotoxic activity; however, it cannot be used in its pure form due to its toxicity and generation of many side effects. Therefore, it practically remains clinically unusable. Currently, high effort is focused on attempts to synthesize analogs of PTOX that have better properties for therapeutic use e.g. etoposide (VP-16), teniposide, etopophos. PTOX derivatives are used as anticancer drugs which are showing additional immunosuppressive, antiviral, antioxidant, hypolipemic, and anti-inflammatory effects. In this review, attention is paid to the high potential of the usefulness of in vitro cultures of P. peltatum which can be a valuable source of lignans, including PTOX. In conclusion, the preclinical pharmacological studies in vitro and in vivo confirm the anticancer and chemotherapeutic potential of PTOX and its derivatives. In the future, clinical studies on human subjects are needed to certify the antitumor effects and the anticancer mechanisms to be certified and analyzed in more detail and to validate the experimental pharmacological preclinical studies.
Background:
Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine.
Methods:
TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments.
Results:
TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil.
Conclusion:
Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS.
Natural product compounds have lately attracted interest in the scientific community as a possible treatment for gastrointestinal (GI) cancer, due to their anti-inflammatory and anticancer properties. There are many preclinical, clinical, and epidemiological studies, suggesting that the consumption of polyphenol compounds, which are abundant in vegetables, grains, fruits, and pulses, may help to prevent various illnesses and disorders from developing, including several GI cancers. The development of GI malignancies follows a well-known path, in which normal gastrointestinal cells acquire abnormalities in their genetic composition, causing the cells to continuously proliferate, and metastasize to other sites, especially the brain and liver. Natural compounds with the ability to affect oncogenic pathways might be possible treatments for GI malignancies, and could easily be tested in clinical trials. Resveratrol is a non-flavonoid polyphenol and a natural stilbene, acting as a phytoestrogen with anti-cancer, cardioprotective, anti-oxidant, and anti-inflammatory properties. Resveratrol has been shown to overcome resistance mechanisms in cancer cells, and when combined with conventional anticancer drugs, could sensitize cancer cells to chemotherapy. Several new resveratrol analogs and nanostructured delivery vehicles with improved anti-GI cancer efficacy, absorption, and pharmacokinetic profiles have already been developed. This present review focuses on the in vitro and in vivo effects of resveratrol on GI cancers, as well as the underlying molecular mechanisms of action.
Phytochemicals have attracted attention in the oncological field because they are biologically friendly and have relevant pharmacological activities. Thanks to the intense and unique spicy aroma, garlic is one of the most used plants for cooking. Its consumption is correlated to health beneficial effects towards several chronic diseases, such as cancer, mainly attributable to allicin, a bioactive sulfur compound stored in different plant parts in a precursor form. The objective of this review is to present and critically discuss the chemistry and biosynthesis of allicin, its pharmacokinetic profile, its anticancer mechanisms and molecular targets, and its selectivity towards tumor cells. The research carried out so far revealed that allicin suppresses the growth of different types of tumors. In particular, it targets many signaling pathways associated with cancer development. Future research directions are also outlined to further characterize this promising natural product.
Heterocyclic compounds offer an enormous area for new lead molecules for drug discovery. Till today, efforts are being continuously made to find appropriate treatment for the management of the deadly disease of cancer. Amongst the large number of heterocycles that are found in nature, heterocycles having oxygen obtained noteworthy attention due to their distinctive and pharmacological activities.‘Pyran’ is one of the most significant non-aromatic, six-membered ring composed of one oxygen atom and five carbon atoms. It is considered a privileged structure since pyran and its related derivatives exhibit a wide spectrum of biological activities. Pyran derivatives are found to have excellent anti-cancer properties against various types of cancer. The present review focussed on the current advances in different types of pyran-based derivatives as anti-cancer agents. Various in-vitro (cell based testing), in-vivo (animal based testing) models as well as molecular docking along with results are also covered. A subsection describing briefly natural pyran containing anticancer compounds is also incorporated in the review.
Despite recent advances in the treatment of colorectal cancer (CRC), low patient survival rate due to emergence of drug resistant cancer cells, metastasis and multiple deleterious side effects of chemotherapy, is a cause of public concern globally. To negate these clinical conundrums, search for effective and harmless novel molecular entities for the treatment of CRC is an urgent necessity. Since antimicrobial peptides (AMPs) are part of innate immunity of living beings, it is quite imperative to look for essential attributes of these peptides which may contribute to their effectiveness against carcinogenesis. Once identified, those characteristics can be suitably modified using several synthetic and computational techniques to further enhance their selectivity and pharmacokinetic profiles. Hence, this review analyses scientific reports describing the antiproliferative action of AMPs derived from several sources, particularly focusing on various colon cancer in vitro/in vivo investigations. On perusal of the literature, it appears that AMPs based therapeutics would definitely find special place in CRC therapy in future either alone or as an adjunct to chemotherapy provided some necessary alterations are made in their natural structures to make them more compatible with modern clinical practice. In this context, further in-depth research is warranted in adequate in vivo models.
Ethnopharmacological relevance
Synthetic drugs used for cancer treatment have side effects that may be immunosupressive, can cause liver, kidney and cardiac toxicity, and infertility and ovarian failure, among others. Thus, herbal drugs could be used in the cancer treatment as an adjuvant therapy. Andrographis paniculata (Burm.f.) Nees (AP) is one of the traditional herbs used in different alternative medicinal systems such as Ayurveda, Unani, Chinese, Malayi, Siddha, etc. for the treatment of various disorders and diseases including cancer.
Aim of the study
The aim of writing this review is to highlight the medicinal importance of AP and its main phytoconstituent andrographolide (AG). The main emphasis was given on the anticancer activity of AG, its proposed mechanisms of action, novel approaches used to improve its biopharmaceutical properties with the perspective of evidence-based research, and its development as an adjuvant therapy for cancer treatment in future.
Materials and methods
Literature survey was conducted and research papers were retrieved from different databases such as Pubmed, Google Scholar, ACS, Wiley online library, ScienceDirect, Springer, and Scopus during 1970-2020. Research articles, review articles, and short communications, etc. were used for this purpose. The papers were selected on the basis of exclusion and inclusion criteria.
Results
Different anticancer mechanisms of AG have been reportedly proven such as cell cycle arrest, apoptosis, NF-κβ inhibition, antiangiogenesis, cytokine inhibition, etc. whereas its pharmacokinetic properties showed its highly protein bound nature, Cyt P400 (CYP) inhibition, low aqueous solubility, poor oral bioavailability, etc. Different novel formulations of AG have been investigated to increase its bioavailability for better efficacy.
Conclusion
This review can provide knowledge about the potential applicability of AP or AG as an adjuvant therapy in cancer treatment. Further research is needed before making any conclusion about the efficacy in humans as an adjuvant therapy in cancer.
The heterocyclic compounds have a great significance in medicinal chemistry because they have extensive biological activities. Cancer is globally the leading cause of death and it is a challenge to develop an appropriate treatment for the management of cancer. Continuous efforts are being made to find a suitable medicinal agent for cancer therapy. Nitrogen-containing heterocycles have received noteworthy attention due to their wide and distinctive pharmacological activities. One of the most important nitrogen-containing heterocycles in medicinal chemistry is ‘quinazoline’ that possesses a wide spectrum of biological properties. This scaffold is an important pharmacophore and is considered a privileged structure. The various substituted quinazolines displayed anticancer activity against different types of cancer. This review highlights the recent advances in quinazoline based molecules as anticancer agents. Several in-vitro and in-vivo models used along with the results are also included. A subpart briefing natural quinazoline containing anticancer compounds is also incorporated in the review.
Ethnopharmacological relevance
Licorice has been commonly used in traditional Chinese medicine for treatment of gastric, liver, and respiratory disease conditions for more than two thousand years. It is a major component of several Chinese patent medicines certificated by National Medical Products Administration that possess great anticancer activities.
Aim of the study
To comprehensively summarize the anticancer activities of licorice flavonoids, explain the underlying molecular mechanisms, and assess their therapeutic potentials and side-effects.
Methods
PubMed, Research Gate, Web of Science, Google Scholar, academic journals, and Science Direct were used as information sources, with the key words of “anticancer”, “licorice”, “flavonoids”, and their combinations, mainly from 2000 to 2019.
Results
Sixteen licorice flavonoids are found to possess anticancer activities. These flavonoids inhibit cancer cells through blocking cell cycle and regulating multiple signaling pathways. The major pathways targeted by licorice flavonoids include: the MAPK pathway, PI3K/AKT pathway, NF-κB pathway, death receptor - dependent extrinsic signaling pathway, and mitochondrial apoptotic pathway.
Conclusion
Licorice flavonoids are a group of versatile molecules that have pleiotropic effects on cell growth, survival and cell signaling. Many of the flavonoids possess inhibitory activities toward cancer cell growth and hence have a great therapeutic potential in cancer treatment. However, additional preclinical studies are still needed to assess their in vivo efficacy and possible toxicities. It is also imperative to evaluate the effects of licorice flavonoids on the metabolism of other drugs and explore the potential synergistic mechanism.
In recent years, natural products have increasingly attracted more attention because of their potential anticancer activity and low intrinsic toxicity. Hispidulin is a natural flavonoid with a wide range of biological activities, including anti-inflammatory, antifungal, antiplatelet, anticonvulsant, anti-osteoporotic, and notably anticancer activities. Numerous in vivo and in vitro studies have shown that hispidulin, as a potential anticancer drug, affects cell proliferation, apoptosis, cell cycle, angiogenesis, and metastasis. Moreover, hispidulin exhibits synergistic anti-tumor effects when combined with some common clinical anticancer drugs (e.g., gemcitabine, 5-fluoroucil, sunitinib, temozolomide, and TRAIL). The combination of hispidulin and chemotherapeutic drugs reduces the efflux of chemotherapeutic drugs, enhances the chemosensitivity of cancer cells, and reverses drug resistance. Herein, we outlined the anticancer effects of hispidulin in various cancers and its intracellular molecular targets and related mechanisms of its anticancer activity. Based on the available literature, it can be established that hispidulin has significant potential to become an important complementary medicine for cancer prevention and treatment. However, more in-depth in vitro and in vivo studies should be conducted to support its translation from bench to bedside.
Cancer can arise due to mutations in numerous pathways present in our body and thus has many alternatives for getting aggravated. Due to this attribute, it gets difficult to treat cancer patients with monotherapy alone and has a risk of not being eliminated to the full extent. This necessitates the introduction of combinatorial therapy as it employs cancer treatment using more than one method and shows a greater success rate. Combinatorial therapy involves a complementary combination of two different therapies like a combination of radio and immunotherapy or a combination of drugs that can target more than one pathway of cancer formation like combining CDK targeting drugs with Growth factors targeting drugs. In this review, we discuss the various aspects of cancer which include, its causes; four regulatory mechanisms namely: apoptosis, cyclin-dependent kinases, tumor suppressor genes, and growth factors; some of the pathways involved; treatment: monotherapy and combinatorial therapy and combinatorial drug formulation in chemotherapy. The present review gives a holistic account of the different mechanisms of therapies and also drug combinations that may serve to not only complement the monotherapy but can also surpass the resistance against monotherapy agents.
Introduction
Nelarabine is a purine analogue approved for the treatment of patients with T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukaemia (T-ALL) that have relapsed or are refractory to two previous chemotherapy regimens. Adverse reactions to nelarabine include neurological toxicity, the pathophysiological mechanisms of which are unknown, although the administration of intrathecal therapy at therapeutic doses given concomitantly with high-dose systemic chemotherapy that crosses the blood–brain barrier may potentiate neurotoxicity.
Case report
We report a case of a 29-year-old woman with a diagnosis of relapsed T-ALL who developed severe myelopathy and polyneuropathy of toxic origin that led to paraplegia, upper-limb paresis, and dysautonomia after the first cycle of nelarabine.
Management and outcome
Rehabilitation and pharmacological treatments were initiated early, but no evidence of a significant clinical change was obtained.
Discussion
Neurotoxicity is a dose-dependent side effect of nelarabine. It is therefore important to consider previously administered neurotoxic drugs before using nelarabine and to monitor patients closely so as to be able to act promptly in case of toxicity. In accordance with the data obtained and based on the Naranjo algorithm, the adverse reaction could be considered possible.