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Upregulation of p53 Expression in Patients with Colorectal Cancer by Administration of Curcumin
Abstract
Biological therapies can be beneficial in cancer patients. The present study aims to examine the inhibitory mechanism of curcumin on cancer cells in patients with colorectal cancer. The results showed that curcumin administration increased body weight, decreased serum TNF-alpha levels, increased apoptotic tumor cells, enhanced expression of p53 molecule in tumor tissue, and modulated tumor cell apoptotic pathway. We conclude that the curcumin treatment improves the general health of patients with colorectal cancer via the mechanism of increased p53 molecule expression in tumor cells and consequently speeds up tumor cell apoptosis.
... In addition, supplementation with 360 milligrams three times daily increased the expression of the p53 protein, an essential protein in regulating the cell cycle and induction of programmed cell death (Z. He et al. 2011). This led to an increase in the amount of apoptosis that was induced in patients with colon cancer (Z. ...
... This led to an increase in the amount of apoptosis that was induced in patients with colon cancer (Z. He et al. 2011). In addition to this, it decreased TNF-α levels by enhancing the patients' overall inflammatory condition (Z. ...
... In addition to this, it decreased TNF-α levels by enhancing the patients' overall inflammatory condition (Z. He et al. 2011). ...
... Zhen et. al. analyzed CRC tissue for DNA fragmentation and apoptosis in light of this idea [197]. Curcumin therapy in CRC patients caused cancer cell death, similar to what was seen in animal studies [196], and this might lower the number of cancer cells in tumors. ...
... Curcumin therapy in CRC patients caused cancer cell death, similar to what was seen in animal studies [196], and this might lower the number of cancer cells in tumors. This investigation found that decreasing the number of cancer cells was associated with better weight loss and lower levels of tumor necrosis factor alpha (TNF-α) in the blood [197]. ...
... Proposed tumor suppressor p53 controls both mitochondria-dependent and mitochondria-independent apoptosis pathways and acts as an apoptosis inducer in response to numerous stresses, including DNA damage, hypoxia, and oncogenetic activation [198]. From this study it may be assumed that curcumin administration induces apoptosis in cancer cells since we detected an increase in the percentage of apoptotic cells in colorectal cancer following curcumin therapy [197]. ...
Abnormalities in the mitogen-activated protein kinase (MAPK) signaling pathway are a key contributor to the carcinogenesis process and have therefore been implicated in several aspects of tumorigenesis, including cell differentiation, proliferation, invasion, angiogenesis, apoptosis, and metastasis. This pathway offers multiple molecular targets that may be modulated for anticancer activity and is of great interest for several malignancies. Polyphenols from various dietary sources have been observed to interfere with certain aspects of this pathway and consequently play a substantial role in the development and progression of cancer by suppressing cell growth, inactivating carcinogens, blocking angiogenesis, causing cell death, and changing immunity. A good number of polyphenolic compounds have shown promising outcomes in numerous pieces of research and are currently being investigated clinically to treat cancer patients. The current study concentrates on the role of the MAPK pathway in the development and metastasis of cancer, with particular emphasis on dietary polyphenolic compounds that influence the different MAPK sub-pathways to obtain an anticancer effect. This study aims to convey an overview of the various aspects of the MAPK pathway in cancer development and invasion, as well as a review of the advances achieved in the development of polyphenols to modulate the MAPK signaling pathway for better treatment of cancer.
... The clinical data on turmeric are scarce. In patients with colorectal cancer, turmeric reduced weight loss and decreased serum inflammatory parameters [39]. A phase II trial involving 44 patients claimed that 30-day turmeric therapy might reduce tumor size [40]. ...
... He et al. (2011) [39],Carroll et al. (2011) [40] ...
... He et al. (2011) [39],Carroll et al. (2011) [40] ...
Cancer is the second leading cause of death worldwide, after cardiovascular diseases. Increasing patients’ awareness and providing easier access to public information result in greater interest in alternative anticancer or unproven supportive therapies. Fear of cancer and limited trust in the treating physician are also important reasons leading patients to seek these methods. Trust and good communication are essential to achieving truthful collaboration between physicians and patients. Given the popularity of CAM, better knowledge about these alternative practices may help oncologists discuss this issue with their patients. This article objectively reviews the most common unconventional therapies used by cancer patients.
... After reading of articles, 14 were excluded due to differences such as administration of curcumin through oral, topical or mouthwash routes without subsequent ingestion, no access to the full study, lack of data and non-randomized studies. A schematic diagram of the search strategy is depicted in Figure 2. Of the six eligible studies, three reported the effect of curcumin on anti-inflammatory profile (He et al., 2011;Panahi et al., 2014;Thomas et al., 2014), one described reduction in dermatitis after radiotherapy (Ryan et al., 2013), three showed modification of PSA ( one study reported an effect on the profile of antioxidant enzymes (Hejazi et al., 2016). A total of 450 adults, comprising 259 individuals in intervention groups and 191 in control groups were included. ...
... The main characteristics of the studies are described in Table I. Four studies used curcumin alone (He et al., 2011;Hejazi et al., 2016;Panahi et al., 2014;Ryan et al., 2013), whereas in two studies curcumin was associated with other nutrients (Van Die et al., 2017;Thomas et al., 2014). ...
... In the study by He et al. (2011), there was a significant reduction in TNF-α percentage levels in patients treated with curcumin after 10 days of treatment (p <0.05). The results showed a negative correlation between body weight gain of patients with colorectal CA in curcumin capsule use and decreased serum levels of TNF-α (r = -0.40 ...
Feeding with high levels of phytochemicals, including curcumin, may be a therapeutic option for diseases such as cancer which is a public health problem. The aim of this study was to systematically review the results of clinical trials investigating the effect of oral curcumin supplementation on anti-inflammatory and antioxidant profiles, reduction of PSA levels and degree of dermatitis in radiotherapy treatment in cancer patients. The review was carried out based on the items of the PRISMA Statement. A bias risk assessment was performed according to Cochrane Collaboration criteria. Six studies met the eligibility criteria and were included in the systematic review. The results of this study are based on those obtained in the literature on the effect of curcumin on the anti-inflammatory profile, on reducing dermatitis, on PSA alteration and on anti-oxidant profile for a total of 450 individuals, comprising 259 in the intervention group and 191 in the control group. Some studies have reported improvement in biochemical and clinical indicators, with limited adverse effects and good tolerance. It was not possible to determine, with the desired degree of evidence, the effect of curcumin supplementation in the treatment of cancer patients. It is important to consider the great heterogeneity and methodological weaknesses of the studies, and that it was not possible to perform a meta-analysis of the data available in the literature.
... Furthermore, curcumin inhibited CRC growth by decreasing proinflammatory TNF-α and enhancing pro-apoptotic p53 [59]. At the molecular level, an interruption of the intercellular, tumor-and inflammation-promoting cross-talk between different components of the tumor microenvironment is particularly relevant, with fortunately modulatory support from secondary plant compounds such as resveratrol, curcumin, and calebin A [7,60,61]. ...
... The turmeric compounds curcumin and calebin A have shown strong anti-CRC effects preclinically [7,8]. While this was confirmed clinically for curcumin [59], calebin A has not been studied in this respect. In the following, we summarized the modes of action of both curcuminoids in CRC cells. ...
Colorectal cancer (CRC) is one of the leading malignant diseases worldwide with a high rate of metastasis and poor prognosis. Treatment options include surgery, which is usually followed by chemotherapy in advanced CRC. With treatment, cancer cells could become resistant to classical cytostatic drugs such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and irinotecan, resulting in chemotherapeutic failure. For this reason, there is a high demand for health-preserving re-sensitization mechanisms including the complementary use of natural plant compounds. Calebin A and curcumin, two polyphenolic turmeric ingredients derived from the Asian Curcuma longa plant, demonstrate versatile anti-inflammatory and cancer-reducing abilities, including CRC-combating capacity. After an insight into their epigenetics-modifying holistic health-promoting effects, this review compares functional anti-CRC mechanisms of multi-targeting turmeric-derived compounds with mono-target classical chemotherapeutic agents. Furthermore, the reversal of resistance to chemotherapeutic drugs was presented by focusing on calebin A's and curcumin's capabilities to chemosensitize or re-sensitize CRC cells to 5-FU, oxaliplatin, cisplatin, and irinotecan. Both polyphenols enhance the receptiveness of CRC cells to standard cytostatic drugs converting them from chemoresistant into non-chemoresistant CRC cells by modulating inflammation, proliferation, cell cycle, cancer stem cells, and apoptotic signaling. Therefore, calebin A and curcumin can be tested for their ability to overcome cancer chemoresistance in preclinical and clinical trials. The future perspective of involving turmeric-ingredients curcumin or calebin A as an additive treatment to chemotherapy for patients with advanced metastasized CRC is explained.
... Due to CUR chemical characteristics, it is considered to be a potent anti-inflammatory phytochemical that can interact with different inflammatory pathways that generated wide range pre-clinical and clinical therapeutic potentials for CUR [9,10]. In the past decade, a growing interest was noticed in CUR-based therapies in prophylaxis and treatment for different diseases, including CVD (atherosclerosis, diabetic cardiomyopathy, arrhythmia, hypertrophic cardiomyopathy, and heart failure) [11][12][13][14][15][16][17][18][19], cancer (colon cancer, breast cancer, and multiple myeloma) [20][21][22][23][24][25][26][27], neurodegenerative diseases (Parkinson's, Alzheimer's disease, and multiple sclerosis) [8,[28][29][30], autoimmune diseases (osteoarthritis and rheumatoid arthritis) [31,32], psychological disorders [33][34][35][36][37], diabetes [38][39][40], pulmonary diseases [41][42][43], gastrointestinal disorders (gastric ulcers, indigestion, and dyspepsia) [44][45][46][47][48], ophthalmic disorders [49][50][51], and skin disorders [52][53][54]. ...
... This effect is attributable to inhibition of cardiomyocyte Due to CUR chemical characteristics, it is considered to be a potent anti-inflammatory phytochemical that can interact with different inflammatory pathways that generated wide range pre-clinical and clinical therapeutic potentials for CUR [9,10]. In the past decade, a growing interest was noticed in CUR-based therapies in prophylaxis and treatment for different diseases, including CVD (atherosclerosis, diabetic cardiomyopathy, arrhythmia, hypertrophic cardiomyopathy, and heart failure) [11][12][13][14][15][16][17][18][19], cancer (colon cancer, breast cancer, and multiple myeloma) [20][21][22][23][24][25][26][27], neurodegenerative diseases (Parkinson's, Alzheimer's disease, and multiple sclerosis) [8,[28][29][30], autoimmune diseases (osteoarthritis and rheumatoid arthritis) [31,32], psychological disorders [33][34][35][36][37], diabetes [38][39][40], pulmonary diseases [41][42][43], gastrointestinal disorders (gastric ulcers, indigestion, and dyspepsia) [44][45][46][47][48], ophthalmic disorders [49][50][51], and skin disorders [52][53][54]. ...
Cardiovascular diseases (CVD) compromises a group of heart and blood vessels disorders with high impact on human health and wellbeing. Curcumin (CUR) have demonstrated beneficial effects on these group of diseases that represent a global burden with a prevalence that continues increasing progressively. Pre- and clinical studies have demonstrated the CUR effects in CVD through its anti-hypercholesterolemic and anti-atherosclerotic effects and its protective properties against cardiac ischemia and reperfusion. However, the CUR therapeutic limitation is its bioavailability. New CUR nanomedicine formulations are developed to solve this problem. The present article aims to discuss different studies and approaches looking into the promising role of nanotechnology-based drug delivery systems to deliver CUR and its derivatives in CVD treatment, with an emphasis on their formulation properties, experimental evidence, bioactivity, as well as challenges and opportunities in developing these systems.
... Gardeazabal et al. [90] performed a prospective Mediterranean cohort study to find an association between polyphenol intake and breast cancer. They experimental on 10,713 Spanish women (middle-aged) and reported that [28,45,49,57,65,70] Suppress serum level of TNF-α and expression of p53 [92] daily consumption of polyphenols (482-893 mg/L) significantly reduced the higher risk of breast cancer in postmenopausal women. Fabian et al. [91] performed experiments on 19 women to identify the effects of flaxseed powder and muffins on breast cancer patients and revealed that daily consumption of flaxseed powder and muffins (25 g daily) for up to 5 weeks significantly inhibited the breast cancer risk by inducing apoptosis and inhibiting cell proliferation. ...
... Similarly, an 80% reduction of breast cancer risk was reported in 45 premenopausal women after daily consumption of lignan (50 mg) up to one year [91]. Another study described that a significant reduction of serum TNF-α and expression of p53 was reported in 126 colorectal cancer patients after daily intake of curcumin (360 mg thrice daily) up to 30 days [92]. The accumulative data revealed that Gierach et al. [93] experimented on 198,404 women (age between 50 and 71) to find the association between breast cancer and caffeine and reported that caffeine has no association in postmenopausal women. ...
Natural products, especially polyphenols (phenolic acids, lignans, and stilbenes) are suggested to be more potent anticancer drugs because of their no or less adverse effects, excess availability, high accuracy, and secure mode of action. In the present review, potential anticancer mechanisms of action of some polyphenols including phenolic acids, lignans, and stilbenes are discussed based on clinical, epidemiological, in vivo, and in vitro studies. The emerging evidence revealed that phenolic acids, lignans, and stilbenes induced apoptosis in the treatment of breast (MCF-7), colon (Caco-2), lung (SKLU-1), prostate (DU-145 and LNCaP), hepatocellular (hepG-2), and cervical (A-431) cancer cells, cell cycle arrest (S/G2/M/G1-phases) in gastric (MKN-45 and MKN-74), colorectal (HCT-116), bladder (T-24 and 5637), oral (H-400), leukemic (HL-60 and MOLT-4) and colon (Caco-2) cancer cells, and inhibit cell proliferation against the prostate (PC-3), liver (LI-90), breast (T47D and MDA-MB-231), colon (HT-29 and Caco-2), cervical (HTB-35), and MIC-1 cancer cells through caspase-3, MAPK, AMPK, Akt, NF-κB, Wnt, CD95, and SIRT1 pathways. Based on accumulated data, we suggested that polyphenols could be considered as a viable therapeutic option in the treatment of cancer cells in the near future.
... It has also been suggested to induce apoptosis by regulating several transcription factors, like p53, Erg-1, AP-1, β-catenin, Hif-1, Notch-1, and PPAR-α causing the down-regulation of Akt, EGFR, cMET cyclin D1, in CL-5 xenograft tumors (Lee et al. 2011). Recent findings from a number of studies suggest that CUR may be able to prevent metastasis by regulating multiple signaling pathways in a manner for which the underlying mechanisms are as of yet unclear (Zong et al. He et al. (2011) 2012). The NF-B signaling pathway has also been shown to be a crucial CUR-regulated mechanism (Zong et al. 2012). ...
Encapsulating curcumin (CUR) in nanocarriers such as liposomes, polymeric micelles, silica nanoparticles, protein-based nanocarriers, solid lipid nanoparticles, and nanocrystals could be efficient for a variety of industrial and biomedical applications. Nanofibers containing CUR represent a stable polymer-drug carrier with excellent surface-to-volume ratios for loading and cell interactions, tailored porosity for controlled CUR release, and diverse properties that fit the requirements for numerous applications. Despite the mentioned benefits, electrospinning is not capable of producing fibers from multiple polymers and biopolymers, and the product's effectiveness might be affected by various machine- and material-dependent parameters like the voltage and the flow rate of the electrospinning process. This review delves into the current and innovative recent research on nanofibers containing CUR and their various applications.
... There has been a growing interest in using traditional herbal medicines to create new drugs in recent years (Boroushaki et al., 2015;Dehnamaki et al., 2019;Zamanian et al., 2021). Research suggests that regular consumption of natural products can enhance patient well-being (He et al., 2011;Patel et al., 2010;Shokrzadeh et al., 2018). ...
Colon cancer (CC) is one of the most common and deadly cancers worldwide. Oncologists are facing challenges such as development of drug resistance and lack of suitable drug options for CC treatment. Flavonoids are a group of natural compounds found in fruits, vegetables, and other plant‐based foods. According to research, they have a potential role in the prevention and treatment of cancer. Apigenin is a flavonoid that is present in many fruits and vegetables. It has been used as a natural antioxidant for a long time and has been considered due to its anticancer effects and low toxicity. The results of this review study show that apigenin has potential anticancer effects on CC cells through various mechanisms. In this comprehensive review, we present the cellular targets and signaling pathways of apigenin indicated to date in in vivo and in vitro CC models. Among the most important modulated pathways, Wnt/β‐catenin, PI3K/AKT/mTOR, MAPK/ERK, JNK, STAT3, Bcl‐xL and Mcl‐1, PKM2, and NF‐kB have been described. Furthermore, apigenin suppresses the cell cycle in G2/M phase in CC cells. In CC cells, apigenin‐induced apoptosis is increased by inhibiting the formation of autophagy. According to the results of this study, apigenin appears to have the potential to be a promising agent for CC therapy, but more research is required in the field of pharmacology and pharmacokinetics to establish the apigenin effects and its dosage for clinical studies.
... According to the results, curcumin could decrease the levels of TNF-alpha in serum, which intuitively improve the conditions of patients. As a result, curcumin could not only promote cell apoptosis, but also enhance the level of p53 molecules in colorectal tissues [31]. In familial adenomatous polyposis (FAP), which would eventually develop into colorectal cancer, both the conventional managements with non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 showed severe adverse effects. ...
In the US, colon cancer has the third most mortality. Though new managements have reported upgraded prognosis, the five-year survival rates of patients with general or metastatic colon cancer are still unsatisfied at 64.7% and 20%, respectively. As a result, more innovative therapies or drugs with high efficacy should be developed. Curcumin, a natural chemical compound, is now in the spotlight of both preclinical and clinical trials on colon cancer. It not only exerts exceptional anti-cancer effects, but also anti-inflammatory and antiviral bio-activities. However, curcumin shows low bioavailability when orally administered. To resolve this issue, nanoparticles have been widely utilized. In this review, we precisely summarize the effects of curcumin on colon cancer in both preclinical and clinical studies. In vitro studies, curcumin could arrest cell cycle at the G2/M phase as well as part of the G1 phase, and induce cell apoptosis by binding to targeted molecules. Except for this, epigenetic alterations could also induce colon cancer. Both in vitro and in vivo studies have proved that curcumin could remarkably influence the prognosis. Moreover, genetically designed murine models which were orally administered with curcumin demonstrated satisfactory effects on colon cancer induced by different factors. More importantly, curcumin alone or as an adjuvant showed satisfactory results in numerous clinical trials. In conclusion, curcumin demonstrated outstanding anti-cancer activity against colon cancer.
... In addition, CUR treatment inactivated the PI3K pathway (Fu et al., 2018). In addition, the capsule form of CUR administration (360 mg) in CRC patients decreased TNF-α levels in serum, increased their body weight, augmented apoptosis of tumor cells, and upregulated p53 in tumor tissue (He et al., 2011). ...
Liver cancer is the sixth most prevalent cancer and ranks third in cancer-related death, after lung and colorectal cancer. Various natural products have been discovered as alternatives to conventional cancer therapy strategies, including radiotherapy, chemotherapy, and surgery. Curcumin (CUR) with antiinflammatory, antioxidant, and antitumor activities has been associated with therapeutic benefits against various cancers. It can regulate multiple signaling pathways, such as PI3K/Akt, Wnt/β-cate-nin, JAK/STAT, p53, MAPKs, and NF-ĸB, which are involved in cancer cell proliferation , metastasis, apoptosis, angiogenesis, and autophagy. Due to its rapid metabolism, poor oral bioavailability, and low solubility in water, CUR application in clinical practices is restricted. To overcome these limitations, nanotechnology-based delivery systems have been applied to use CUR nanoformulations with added benefits, such as reducing toxicity, improving cellular uptake, and targeting tumor sites. Besides the anticancer activities of CUR in combating various cancers, especially liver cancer, here we focused on the CUR nanoformulations, such as micelles, liposomes, polymeric, metal, and solid lipid nanoparticles, and others, in the treatment of liver cancer.
... Curcumin was also reported to induce p53 and Bax expression in patients with colorectal cancer, causing apoptosis and DNA fragmentation and suppressing TNF-α and Bcl-2. The treatment also improved patients' general health at a dosage of 360 mg thrice daily 262 . The combination of curcumin, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in colorectal liver metastases reduced stem cell markers, such as aldehyde dehydrogenase and CD133 263 . ...
Turmeric (Curcuma longa) has been used for thousands of years for the prevention and treatment of various chronic diseases. Curcumin is just one of >200 ingredients in turmeric. Almost 7000 scientific papers on turmeric and almost 20,000 on curcumin have been published in PubMed. Scientific reports based on cell culture or animal studies are often not reproducible in humans. Therefore, human clinical trials are the best indicators for the prevention and treatment of a disease using a given agent/drug. Herein, we conducted an extensive literature survey on PubMed and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The keywords "turmeric and clinical trials" and "curcumin and clinical trials" were considered for data mining. A total of 148 references were found to be relevant for the key term "turmeric and clinical trials", of which 70 were common in both PubMed and Scopus, 44 were unique to PubMed, and 34 were unique to Scopus. Similarly, for the search term "curcumin and clinical trials", 440 references were found to be relevant, of which 70 were unique to PubMed, 110 were unique to Scopus, and 260 were common to both databases. These studies show that the golden spice has enormous health and medicinal benefits for humans. This Review will extract and summarize the lessons learned about turmeric and curcumin in the prevention and treatment of chronic diseases based on clinical trials.
... After treatment with curcumin, the samples from cancer patients depict increased body weight, lower TNF-alpha, enhanced apoptotic tumour cells and increased levels of p53 in tumour tissue (Ref. 157). The study report concluded that curcumin administration improves the cancer patient's health profile by altering the expression of p53 molecule. ...
The human oral cavity is comprised of dynamic and polynomial microbes which uniquely reside in the microenvironments of oral cavities. The cumulative functions of the symbiotic microbial communities maintain normal homeostasis; however, a shifted microbiota yields a dysbiosis state, which produces local and systemic diseases including dental caries, periodontitis, cancer, obesity and diabetes. Recent research reports claim that an association occurs between oral dysbiosis and the progression of different types of cancers including oral, gastric and pancreatic ones. Different mechanisms are proposed for the development of cancer, such as induction of inflammatory reactions, production of carcinogenic materials and alteration of the immune system. Medications are available to treat these associated diseases; however, the current strategies may further worsen the disease by unwanted side effects. Natural-derived polyphenol molecules significantly inhibit a wide range of systemic diseases with fewer side effects. In this review, we have displayed the functions of the oral microbes and we have extended the report regarding the role of polyphenols in oral microbiota to maintain healthy conditions and prevention of diseases with emphasis on the treatment of oral microbiota-associated cancer.
... In another study, subjects were given curcumin capsules at three different doses (3.6, 1.8, and 0.45 g/day) for 7 days and found that curcumin supplementation reduced the prostaglandin E2 levels [101]. Curcumin/standardized turmeric extract supplementation also reduced the M 1 G levels [102], aberrant crypt foci [103], improved body weight, reduced serum inflammatory biomarkers, and induced p53 protein expression [104]. The supplementation of curcuminoid is also found to be effective in pancreatic cancer by reducing the lipid peroxidation [105], mild anticancer activities [106], etc. Supplementation of turmeric extracts standardized to curcuminoids is also found to be effective in controlling the symptoms and biomarkers associated with pancreatic cancer. ...
Natural phytochemicals derived from plant extracts are used for a wide variety of applications, and research interest is going on a high pace utilizing the efficacy of various bioactive components. Consumer consciousness has led the scientists to deliver value-added products with the incorporation of various plant extracts. Turmeric, the “golden spice” is known from the Vedic cultures where it was used for regular homemade uses and for treating various disorders. It is one of the herbs which finds use from kitchen to clinical studies. Curcuminoids find their application to deliver health benefits, even in different forms. Innovative nutraceutical companies have focused on developing novel technologies to deliver value-added products. The chapter tries to present an overview on the various applications of curcuminoids in functional foods, nutraceuticals, molecular targets, and innovative technologies.
... A clinical randomized study assessed the anticancer effect of curcumin on CRC cells in 126 patients (He et al., 2011). Half of the patients received oral curcumin capsules at a dose of 360 mg/ Frontiers in Pharmacology frontiersin.org ...
Esophageal cancer (EC) is a common tumor of the gastrointestinal system and a major threat to human health. The etiology and incidence of EC vary depending on the type of pathology. Owing to the unique physiological structure of the esophagus and the poor biological behavior of EC, the treatment modalities available are limited, and the prognosis of patients is relatively poor. Curcumin is a type of natural phytochemical belonging to the class of phenolic compounds. It exerts favorable anticancer effects on various cancers. A growing body of evidence indicates that curcumin suppresses tumor development and progression by inhibiting tumor cell proliferation, invasion, and migration, thus inducing apoptosis, regulating microRNA expression, reversing multidrug resistance, and inducing sensitivity to the therapeutic effect of chemoradiotherapy. Multiple cellular molecules, growth factors, and genes encoding proteins participating in different signaling pathways interact with each other to contribute to the complex and orderly anticancer effect. The efficacy and safety of curcumin have been established in preclinical studies for EC and clinical trials for other cancers. However, the low bioavailability of curcumin limits its clinical application. Therefore, the modification of curcumin analogs, the combination of curcumin with other drugs or therapies, and the use of novel nanocarriers have been widely investigated to improve the clinical effects of curcumin in EC.
... This treatment significantly reduced the number and size of ileal and rectal adenomas, compared with the baseline (60.4% and 50.9%, respectively), without toxicity. Other studies demonstrated that a daily dose of curcumin (3.6 g in capsule form) improves the general health of colorectal cancer patients by increasing p53 molecule expression in tumor cells, and consequently, inducing tumor cell apoptosis [86,120]. ...
Given the stochastic complexity of cancer diseases, the development of chemotherapeutic drugs is almost limited by problems of selectivity and side effects. Furthermore, an increasing number of protective approaches have been recently considered as the main way to limit these pathologies. Natural bioactive compounds, and particularly dietary phenolic compounds, showed major protective and therapeutic effects against different types of human cancers. Indeed, phenolic substances have functional groups that allow them to exert several anti-cancer mechanisms, such as the induction of apoptosis, autophagy, cell cycle arrest at different stages, and the inhibition of telomerase. In addition, in vivo studies show that these phenolic compounds also have anti-angiogenic effects via the inhibition of invasion and angiogenesis. Moreover, clinical studies have already highlighted certain phenolic compounds producing clinical effects alone, or in combination with drugs used in chemotherapy. In the present work, we present a major advance in research concerning the mechanisms of action of the different phenolic compounds that are contained in food medicinal plants, as well as evidence from the clinical trials that focus on them.
... It has been reported that curcumin can induce apoptosis in human colon cancer HT29 cells [64]. In chemo-resistant CRC cells, curcumin can enhance the therapeutic potential of conventional chemotherapeutic drugs by inhibiting proliferative targets, including cyclin D1, NF-κB, phosphoinositide 3-kinase and Src [65]. Resveratrol, a natural stilbene found in wine and grapes, has been reported to inhibit signaling pathways involved in [66]. ...
Colorectal cancer (CRC) is a disease with high prevalence and mortality. Estimated preventability for CRC is approximately 50%, indicating that altering modifiable factors, including diet and body weight, can reduce CRC risk. There is strong evidence that dietary factors including whole grains, high-fiber, red and processed meat, and alcohol can affect the risk of CRC. An alternative strategy for preventing CRC is use of a chemopreventive supplement that provides higher individual exposure to nutrients than what can be obtained from the diet. These include calcium, vitamin D, folate, n-3 polyunsaturated fatty acids, and phytochemicals. Several intervention trials have shown that these dietary chemopreventives have positive protective effects on development and progression CRC. Research on chemoprevention with phytochemicals that possess anti-inflammatory and/or, anti-oxidative properties is still in the preclinical phase. Intentional weight loss by bariatric surgery has not been effective in decreasing long-term CRC risk. Physicians should perform dietary education for patients who are at high risk of cancer for changing their dietary habits and behaviour. An increased understanding of the role of individual nutrients linked to the intestinal micro-environment and stages of carcinogenesis would facilitate the development of the best nutritional formulations for preventing CRC.
... This ties in with the fact that advanced-age primary tumors are characterized by increased EGFR expression and these patients may have developed primary tumors at late stages of their life, leading to worse prognosis. 8 Clinical Medicine Insights: Oncology Regarding IDH1, a 2012 study by Sipayya et al 27 found that GBM patients had 9.7% (7/72) IDH1-positive specimens in a total of 195 gliomas. However, another study correlating the expression of IDH1 mutant protein using IHC detected no positive samples in GBM patients of India. ...
Introduction
Glioblastoma multiforme (GBM) is one of the deadliest cranial tumors occurring in adults. Various biomarkers have been tested for their significance in diagnosis, prognosis, and treatment of GBM. Some well-studied markers in GBM are Isocitrate dehydrogenase 1 (IDH1), Murine double minute 2 (MDM2), Epidermal Growth Factor Receptor (EGFR), and p53. The aim of this study was to investigate the protein expression of these markers in GBM patients of Pakistan.
Methods
A total of 102 surgically resected formalin-fixed paraffin-embedded specimens from patients diagnosed and treated at Aga Khan University Hospital were included in this study. Immunohistochemistry (IHC) for IDH1, MDM2, EGFR, and p53 was performed using Dako EnVision System and respective monoclonal antibodies. Survival analysis was performed to check association of markers protein expression with prognosis in GBM patients.
Results
There were 73 males and 29 females in this study, with a median age of 49 years at the time diagnosis. Overexpression of molecular markers was as follows: 52% for EGFR, 26% for p53, 72% for IDH1, and 83% for MDM2. We did observe that EGFR was significantly associated with increased age of our patients and with worse survival. Age > 40 years was a predictor for worse prognosis as well.
Conclusion
EGFR overexpression and advanced age were worse prognostic indicators.
... The anti-cancer effects of CUR on CRC cells are widely known, which is associated with activation of the apoptotic pathway [20]. Extensive studies on the underlying mechanism of apoptosis by CUR in CRC have reported several molecular targets, including enzymes such as COX-2 [37], SOD and ROS [38], transcription factors (such as catenin, NF-κB, AP-1 and PPAR-γ) [39,40], members of the Bcl-2 family, BH3 protein (such as Bim, Bad and Bid) [41], protease enzymes (such as caspase 3 and caspase 8), death receptors (such as DR5 and Fas) and other important signaling pathways such as p53, phosphoinositide-3 kinase/protein kinase-B (PI3K/Akt), JNK and ER stress [42]. It should be noted that cancer progression is a multiphase, multi-gene and multi-factor process. ...
Background: Colorectal cancer (CRC) continues to be a leading cause of cancer related death in the world and approximately 70 to 75 % of patients with metastatic colorectal cancer survive for up to 1 year after diagnosis. Curcumin (CUR) is a potential chemotherapeutic agent used to treat cancer. There is ample evidence of the inhibitory effects of Hypericum perforatum L. extract (HPE) on cell proliferation and its effects on the induction of apoptosis in various human cancer cell lines. Objective: The purpose of this study was to investigate the proapoptotic effect of HPE and its nanoliposomes (HPE-Lip) and to scrutinize the synergistic and therapeutic potential of HPE/CUR-loaded nanoliposome (HPE/CUR-Lip). Methods: In the present in vitro study, SW1116 and SW48 cell lines were cultured and then treated with different doses of HPE, CUR, bare liposome solely (Lip-Sol), and nanoliposomes loaded with HPE (HPE-Lip), CUR (CUR-Lip) and CUR/HPE (HPE/CUR-Lip) for 24, 48 and 72 hours. Cytotoxicity was measured by MTT assay and apoptosis rate by an annexin-V FITC/propidium iodide double-staining method using flow cytometry. Results: The results showed that cell viability was inhibited in a dose-dependent and time-dependent manner in all groups compared to the control group. The use of nanoliposomes improved the outcomes. HPE/CUR-Lip exhibited higher in vitro cytotoxic and proapoptotic activity against SW1116 and SW48 cell lines (P < 0.05). Conclusion: The findings of this study suggest that the HPE/CUR-Lip complex could provide a potential strategy to achieve a synergistic effect of HPE and CUR in the treatment of colorectal cancer.
... According to this study, curcumin can increase p53 expression in tumor cells and can accelerate apoptosis in CRC patients. 41 Some clinical trials were performed to study the role of curcumin for CRC prevention. One of earliest trials is a phase 2A clinical trial performed by Carroll et al. including 41 patients with eight or more colonic aberrant crypt foci. ...
... However, on account of its quick metabolism and low concentration within tumors, no substantial anticancer effect is observed in vivo following exposure of mice to either 20 or 30 mg/kg 10058-F4 [12]. Curcumin has been used to treat numerous types of cancer, including colorectal cancer, either alone or in conjunction with other treatments [28,29], breast cancer [30,31], lung cancer [32], prostate cancer [33], and liver cancer [34]. e potent antineoplastic properties of curcumin against different cancers are due to proapoptotic, antiproliferative, proapoptotic, and anti-inflammatory mechanisms [15,16,35]. ...
Background:
Pancreatic cancer (PC) stands out as one of the most lethal cancers. Due to late diagnosis, only a fraction of patients can be resected. Although it still has significant adverse effects and poor results, the treatment is connected with better overall survival than the prior treatment. Thus, new alternative therapy for advanced PC is needed. Materials/Methods. The impact of 10058-F4 and curcumin combination therapy on apoptosis and cell growth in SW1990 pancreatic cancer cells were determined in vitro using the CCK-8 assay and flow cytometry of Annexin V-FITC/PI, and the in vivo antitumor effect was determined utilizing SW1990-bearing pancreatic tumor mouse models induced by subcutaneous implantation.
Results:
At concentrations of (10 mol/L+2 mol/L), 10058-F4+curcumin obtained the highest rate of SW1990 cell death, and they had a beneficial effect on SW1990 pancreatic tumor-bearing animals. Furthermore, c-Myc, Akt phosphorylation, and the expression of apoptosis-related molecular were reduced, and the combination therapy modified the expression of apoptosis-related molecular.
Conclusions:
In vitro and in vivo, the combination of 10058-F4 plus curcumin has antipancreatic cancer actions that are substantially effective.
... In a clinical study on patients with CRC, CUR resulted in favorable effects, such as decreased serum tumor necrosis factor (TNF)-α levels, increased apoptotic tumor cells, enhanced expression of the p53 molecule in tumor tissue, and modulation of the tumor cell apoptosis pathway, suggesting that CUR can improve the general health of these patients by increasing p53 expression in tumor cells and enhancing tumor cell apoptosis (He et al. 2011). ...
Epidemiological studies have shown that consumption of green tea, coffee, wine, and curry may contribute to a reduced risk of various cancers. However, there are some cancer site-specific differences in their effects; for example, the consumption of tea or wine may reduce bladder cancer risk, whereas coffee consumption may increase the risk. Animal and cell-based experiments have been used to elucidate the anticancer mechanisms of these compounds, with reactive oxygen species (ROS)-based mechanisms emerging as likely candidates. Chlorogenic acid (CGA), curcumin (CUR), epigallocatechin gallate (EGCG), and resveratrol (RSV) can act as antioxidants that activate AMP-activated protein kinase (AMPK) to downregulate ROS, and as prooxidants to generate ROS, leading to the downregulation of NF-κB. Polyphenols can modulate miRNA (miR) expression, with these dietary polyphenols shown to downregulate tumor-promoting miR-21. CUR, EGCG, and RSV can upregulate tumor-suppressing miR-16, 34a, 145, and 200c, but downregulate tumor-promoting miR-25a. CGA, EGCG, and RSV downregulate tumor-suppressing miR-20a, 93, and 106b. The effects of miRs may combine with ROS-mediated pathways, enhancing the anticancer effects of these polyphenols. More precise analysis is needed to determine how the different modulations of miRs by polyphenols relate to the cancer site-specific differences found in epidemiological studies related to the consumption of foods containing these polyphenols.
... The authors indicated that curcumin therapy, through the mechanism of increased p53 expression in tumor cells and tissues, can improve the ordinary fitness of CRC patients. However, to validate these arguments, further studies are required [76]. ...
Curcumin, an important constituent of turmeric used in the traditional medicinal system has suffered considerable controversy. Classification as pan-assay interference compounds and invalid metabolic panaceas contributed toward its inability as a lead compound. The conclusions were drawn on the basis of various clinical trials that failed to prove the medicinal effect of curcumin. The inclusion of high throughput screening studies also contributed to this entitlement. Still, researchers didn't put an end to explore on cur-cumin probably due to the traditionally accepted role of turmeric in medicines. Extensive investigation on curcumin multiplied enormously and more than 27,000 documents results in Scopus with one click on cur-cumin. It being a pharmacologically significant molecule or "Much Ado about Nothing" will always be debatable. In the present review, we have compiled successful clinical trials with curcumin in several diseased conditions including the results of such clinical trials where the prescribed medicine failed to respond.
... Another study conducted in our laboratory revealed its chemopreventive efficacy against the lung carcinogenesis induced by B (a)P, a potential environmental carcinogen found in cigarette smoke and deep-fried food, in Swiss albino mice (Puliyappadamba et al., 2015). Curcumin treatment has a significant impact on improving the general health of colorectal cancer patients by enhancing expression of p53 molecules in tumour cells and also by promoting the apoptosis of tumour cells (He et al., 2011;Pricci et al., 2020). Curcumin intake causes the down-regulation of NF-kB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells from patients with pancreatic cancer (Dhillon et al., 2008). ...
Cancer chemoprevention approaches are aimed at preventing, delaying, or suppressing tumor incidence using synthetic or natural bioactive agents. Mechanistically, chemopreventive agents also aid in mitigating cancer development, either by impeding DNA damage or by blocking the division of premalignant cells with DNA damage. Several pre-clinical studies have substantiated the benefits of using various dietary components as chemopreventives in cancer therapy. The incessant rise in the number of cancer cases globally is an issue of major concern. The excessive toxicity and chemoresistance associated with conventional chemotherapies decrease the success rates of the existent chemotherapeutic regimen, which warrants the need for an efficient and safer alternative therapeutic approach. In this scenario, chemopreventive agents have been proven to be successful in protecting the high-risk populations from cancer, which further validates chemoprevention strategy as rational and promising. Clinical studies have shown the effectiveness of this approach in managing cancers of different origins. Phytochemicals, which constitute an appreciable proportion of currently used chemotherapeutic drugs, have been tested for their chemopreventive efficacy. This review primarily aims to highlight the efficacy of phytochemicals, currently being investigated globally as chemopreventives. The clinical relevance of chemoprevention, with special emphasis on the phytochemicals, curcumin, resveratrol, tryptanthrin, kaempferol, gingerol, emodin, quercetin genistein and epigallocatechingallate, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity, forms the crux of this review. The majority of these phytochemicals are polyphenols and flavanoids. We have analyzed how the key molecular targets of these chemopreventives potentially counteract the key drivers of chemoresistance, causing minimum toxicity to the body. An overview of the underlying mechanism of action of these phytochemicals in regulating the key players of cancer progression and tumor suppression is discussed in this review. A summary of the clinical trials on the important phytochemicals that emerge as chemopreventives is also incorporated. We elaborate on the pre-clinical and clinical observations, pharmacokinetics, mechanism of action, and molecular targets of some of these natural products. To summarize, the scope of this review comprises of the current status, limitations, and future directions of cancer chemoprevention, emphasizing the potency of phytochemicals as effective chemopreventives.
... Jeong et al. demonstrated the inhibition of NF-kB in CRC cell lines by curcumin [44]. Further, it has been suggested that the antiinflammatory properties of curcuminoids in patients with CRC can be exerted by enhancing the expression of the tumor protein p53 in tumor tissue and modulating the tumor cell apoptotic pathway [45]. In an oxaliplatin/curcumin combination study in vitro, and using an animal model, Yin et al. found that curcumin could inhibit the phosphorylation of transcription factor p65 and Bcl-2 expression and prevent oxaliplatin resistance in CRC through the suppression of TGF-β/ Smads signaling [46]. ...
Background
Colorectal cancer (CRC) is the third and the fourth most common cancer in Iranian men and women, respectively. Curcuminoids are known to exertprotective effects against several kinds of cancers. We aim to assess the effects of curcuminoids on serum pro- and anti-inflammatory cytokines and quality of life in patients with colorectal cancer undergoing chemotherapy.
Material and Methods
This study was a double-blind placebo-controlled trial in patients with CRC (stage 3) aged ≥20 years, who had chemotherapy after the surgery and were referred to Baqiyatallah Oncology Clinic. Patients were randomly assigned to the treatment group receiving curcuminoids capsules (500 mg/day) (n = 36), or the control group taking placebo capsules (n = 36) for 8 weeks. Erythrocyte sedimentation rate (ESR) and serum levels of C-reactive protein (CRP) and 12 pro- and anti-inflammatory cytokines including tumor necrosis factor (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, monocyte chemoattractant protein (MCP-1), interferon γ (IFN-γ), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF)] were measured at baseline and at the end of the intervention. The EORTC-QLQ-C30 instrument was used to assess the quality of life before and after the intervention. Statistical analyses were performed using SPSS software.
Results
A total of 67 subjects completed the study as three and two subjects were lost to follow-up in the curcuminoid and placebo groups, respectively. A significant change in CRP (p = 0.002) and ESR (p = 0.0001) was observed in patients supplemented with curcuminoids at the end of 8 weeks compared to placebo. Moreover, IL-1α showed a decreasing trend after curcuminoid supplementation compared to placebo (p = 0.077). A significant improvement in functional (p = 0.002) and global quality of life (p = 0.020) scales was observed in the curcuminoid group.
Conclusions
The results showed that curcuminoids supplementation for a period of 8 weeks (500 mg/day) can improve ESR and serum levels of CRP in stage-3 CRC subjects and improve the global quality of life and functional scales compared to placebo.
... Administration of curcumin improved the tender joint count (TJC) and swollen joint count (SJC) 155 and prevented the production and function of TNF. 156,157 The inhibitory effects of curcumin on human synovial fibroblast growth occurred through induction of apoptosis and inhibition of PGE2 production in rheumatoid arthritis patients. 155 Treatment with curcumin (500 mg) resulted in the highest percentage of improvement in overall Disease Activity Score (DAS) and American College of Rheumatology (ACR) scores in patients with rheumatoid arthritis. ...
Curcuma longa and its constituents, mainly curcumin, showed various of pharmacological effects in previous studies. This review article provides updated and comprehensive experimental and clinical evidence regarding the effects of C. longa and curcumin on respiratory, allergic, and immunologic disorders. Using appropriate keywords, databases including PubMed, Science Direct, and Scopus were searched until the end of October 2021. C. longa extracts and its constituent, curcumin, showed the relaxant effect on tracheal smooth muscle, which indicates their bronchodilatory effect in obstructive pulmonary diseases. The preventive effects of extracts of C. longa and curcumin were shown in experimental animal models of different respiratory diseases through antioxidant, immunomodulatory, and anti-inflammatory mechanisms. C. longa and curcumin also showed preventive effects on some lung disorders in the clinical studies. It was shown that the effects of C. longa on pulmonary diseases were mainly due to its constituent, curcumin. Pharmacological effects of C. longa extracts and curcumin on respiratory, allergic, and immunologic disorders indicate the possible therapeutic effect of the plant and curcumin on these diseases.
... Further, curcumin enhances the expression of p53, a cell cycle mediator, implicated in the pathophysiology of many malignant tumors including cervical cancer, high-grade ovarian carcinoma, endometrial cancer, and even colorectal cancer particularly in a time and dose-dependent manner [20,21]. ...
Curcumin is a commonly used herbal supplement purported for its antioxidant, anti-inflammatory, and antineoplastic properties. The effects of curcumin supplementation on endometrial lining have been proposed; however, endometrial preparation in the case of frozen-thawed embryo transfer (FET) has not been established. This case series references two scenarios where turmeric was ingested by the patient, and endometrial thickness was subsequently reduced disrupting the FET cycle. Throughout this case series, curcumin's possible interactions with the uterine lining are summarized. Additionally, these cases highlight the importance of physicians' awareness of taking a full history of any herbal remedies or supplements in addition to prescription or over-the-counter medications taken when undergoing treatment for controlled FET cycles or in-vitro fertilization (IVF). To our knowledge, no studies to date have investigated this relationship.
... 228 It has shown benefits in diseases such as inflammatory conditions, kidney conditions, metabolic syndrome and pain, most of which have been attributed to its anti-inflammatory and antioxidant activities. 228 Importantly, it has also demonstrated anti-cancer potentials both preclinically and clinically in oral, 229 breast, 230-233 colorectal, 234 pancreatic, 235 skin 236 as well as head and neck 237 cancers. Specifically, the anti-BC activities of curcumin have been linked to the modulation of cell cycle regulators and metastasis-related markers; the induction of caspase-dependent apoptosis and mitochondrial apoptotic pathway; the suppression of PI3K/ AKT/mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK), NF-κB and β-catenin signalling pathways; the activation of p53 signalling pathway; as well as the inhibition of angiogenesis. ...
Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants' extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: "Natural Product AND Nanoparticle AND Breast Cancer". Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.
Tumor angiogenesis is the formation of new blood vessels to support the growth of a tumor. This process is critical for tumor progression and metastasis, making it an attractive approach to cancer therapy. Natural products derived from plants, animals, or microorganisms exert anti-angiogenic properties and can be used to inhibit tumor growth and progression. In this review, we comprehensively report on the current status of natural products against tumor angiogenesis from four perspectives until March 2023: 1) the role of pro-angiogenic factors and antiangiogenic factors in tumor angiogenesis; 2) the development of anti-tumor angiogenesis therapy (monoclonal antibodies, VEGFR-targeted small molecules, and fusion proteins); 3) the summary of anti-angiogenic natural agents, including polyphenols, polysaccharides, alkaloids, terpenoids, saponins and their mechanisms of action; 4) the future perspectives of anti-angiogenic natural products (bioavailability improvement, testing of dosage and side effects, combination use, and discovery of unique natural-based compounds). Our review aims to better understand the potential of natural products for drug development in inhibiting tumor angiogenesis and further aid the effective transition of these outcomes into clinical trials.
Curcumin, a natural polyphenol, derived from Curcuma longa L. is extensively studied by various researchers across the globe and has established its immense potential in the management of several disorders at clinical level. The underlying mechanism of curcumin involves regulation of various molecular targets, namely, inflammatory cytokines, transcription factor, apoptotic genes, growth factors, oxidative stress biomarkers, and protein kinases. In clinical trials, curcumin as an adjuvant has significantly boost‐up the efficacy of many proven drugs in the management of arthritis, neurodegenerative disorder, oral infection, and gastrointestinal disorders. Moreover, clinical studies have suggested curcumin as an appropriate candidate for the prevention and/or management of various cancers via regulation of signaling molecules including NF‐kB, cytokines, C‐reactive protein, prostaglandin E2, Nrf2, HO‐1, ALT, AST, kinases, and blood profiles. This article highlights plethora of clinical trials that have been conducted on curcumin and its derivatives in the management of several ailments. Besides, it provides recent updates to the investigators for conducting future research to fulfill the current gaps to expedite the curcumin utility in clinical subjects bearing different pathological states.
Introduction:
Curcumin is a naturally occurring compound that has antioxidant properties, acts as a hepatoprotective, and lowers lipid peroxidation. However, curcumin's low solubility and bioavailability are its primary drawbacks and prevent its use as a therapeutic agent. In this study, curcumin nanoparticles will be created using the ultrasonic-assisted extraction method, and their effectiveness against paracetamol-induced changes in ALT, AST, SOD, MDA, and TNF-α will be compared to that of pure curcumin.
Purpose:
This study aimed to determine the hepatoprotective effect of curcumin nanoparticles in paracetamol-induced rats as a model for liver injury.
Methods:
Thirty-six male Wistar rats, aged 6 to 8 weeks, with a minimum weight of 120 grams, were used in an experimental laboratory investigation with a post-test-only group design. Rats in each group received 100 mg/kgBW pure curcumin, 100 mg/kgBW curcumin nanoparticles, and 50 mg/kgBW curcumin nanoparticles for 7 days before paracetamol induction. On day 8, 300 mg/kgBW of paracetamol was intraperitoneally injected to cause liver damage. One of the groups received NAC as an antidote 10 hours after paracetamol induction. Detection of ALT and AST using a Chemistry Analyzer. ELISA approach for the detection of SOD, MDA, and TNF-α. The Roenigk score was calculated by two examiners after the liver histopathology preparations were stained using the Hematoxylin-Eosin method. Post hoc analyses were performed after the One Way Annova and Kruskal Wallis tests to examine the data.
Results:
According to PSA results, the smallest formula that formed curcumin nanoparticles (10.2 nm) was 8 g of curcumin formula mixed with a mixture of Tween 20 4.5 ml, Kolliphor EL 1.5 ml, Propylene Glycol 1.5 ml, and Capryol 90 1 ml for 21 minutes using an ultrasonic process. MDA and TNF-α levels, as well as the liver's histological Roenigk score, were significantly lower in the 100 mg/kgBB pure curcumin group (C100) when compared to the model group (model). The levels of AST, MDA, TNF-α, and the liver histopathology score were significantly lower in the 100 mg/kgBB (NC100) and 50 mg/kgBB (NC50) curcumin nanoparticle groups compared to the model group (model) and pure curcumin group (C100) (p< 0.05).
Conclusion:
Curcumin nanoparticles showed better hepatoprotective ability than pure curcumin.
Background: Colorectal cancer is the most common malignancy in humans, and it is predicted that 145,600 new cases will be diagnosed in the United States by 2019. The bioactive properties of curcuminoids and their synthetic analogs, especially their performance with an anticancer approach in different cancer cell line models, are of interest. In vivo and in vitro studies show their anticancer activity against colon cancer cell lines. Methods: In this descriptive-analytical study, colorectal cancer cells of the Caco2 cell line were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. After calculating the IC 50, the cells were exposed to logarithmic concentrations of curcumin (curcumin) 10, 100, and 500 µg/mL for 24 hours. Finally, the effect of the toxicity of materials and low-power laser combined with melanin was measured by the MTT assay test. Results: The changes in the survival rate of colorectal cancer cells show the effect of curcumin on cell proliferation that is completely dependent on concentration and time. Calculating the survival percentage of cancer cells after treatment with different concentrations for 24, 48, and 72 hours showed that the decrease in viable cells compared to the control sample was significant (P < 0.001). Conclusions: The results showed that the use of curcumin either alone or together with a low-power laser could improve the treatment efficiency against colon cancer. The present review highlights the mechanism of synergistic effect and new delivery methods to improve curcumin's therapeutic potential.
Regarding the multimechanistic nature of cancers, current chemo- or radiotherapies often fail to eradicate disease pathology, and frequent relapses or resistance to therapies occur. Brain malignancies, particularly glioblastomas, are difficult-to-treat cancers due to their highly malignant and multidimensional biology. Unfortunately, patients suffering from malignant tumors often experience poor prognoses and short survival periods. Thus far, significant efforts have been conducted to discover novel and more effective modalities. To that end, modulation of the ubiquitin-proteasome system (UPS) has attracted tremendous interest since it affects the homeostasis of proteins critically engaged in various cell functions, for example, cell metabolism, survival, proliferation, and differentiation. With their safe and multimodal actions, phytochemicals are among the promising therapeutic tools capable of turning the operation of various UPS elements. The present review, along with an updated outline of the role of UPS dysregulation in multiple cancers, provided a detailed discussion on the impact of phytochemicals on the UPS function in malignancies, especially brain tumors.
Abstract: The diarylheptanoid curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione] is one of the phenolic pigments responsible for the yellow colour of turmeric (Curcuma longa L.). This phytochemical has gained much attention in recent years due to its therapeutic potential in cancer. A range of drug delivery approaches have been developed to optimise the pharmacokinetic profile of curcumin and ensure that it reaches its target sites. Curcumin exhibits numerous biological effects, including anti-inflammatory, cardioprotective, antidiabetic, and anti-aging activities. It has also been extensively studied for its role as a cancer chemopreventive and anticancer agent. This review focusses on the role of curcumin in targeting the cell signalling pathways involved in cancer, particularly via modulation of growth factors, transcription factors, kinases and other enzymes, pro-inflammatory cytokines, and pro-apoptotic and anti-apoptotic proteins. It is hoped that this study will help future work on the potential of curcumin to fight cancer.
Cancer is considered as the major public health scourge of the 21st century. Though remarkable strides were made for developing targeted therapeutics, these therapies suffer from lack of efficacy, high cost, and debilitating side effects. Therefore, the search for safe, highly efficacious, and affordable therapies is paramount for establishing a treatment regimen for this deadly disease. Curcumin, a known natural, bioactive polyphenol compound from the spice turmeric (Curcuma longa), has been well documented for its wide range of pharmacological and biological activities. A plethora of literature indicates its potency as an anti-inflammatory and anti-cancer agent. Curcumin exhibits anti-neoplastic attributes via regulating a wide array of biological cascades involved in mutagenesis, proliferation, apoptosis, oncogene expression, tumorigenesis, and metastasis. Curcumin has shown a wide range of pleiotropic anti-proliferative effects in multiple cancers and is a known inhibitor of varied oncogenic elements, including NF-κB, c-myc, cyclin D1, Bcl-2, VEGF, COX-2, NOS, TNF-α, interleukins, and MMP-9. Further, curcumin targets different growth factor receptors and cell adhesion molecules involved in tumor growth and progression, making it a most promising nutraceutical for cancer therapy. To date, curcumin-based therapeutics have completed more than 50 clinical trials for cancer. Though creative experimentation is still elucidating the immense potential of curcumin, systematic validation by proper randomized clinical trials warrants its transition from lab to bedside. Therefore, this chapter summarizes the outcome of diverse clinical trials of curcumin in various cancer types
Gastrointestinal cancer (GIC) poses a serious threat to human health globally. Curcumin (CUR), a hydrophobic polyphenol extracted from the rhizome of Curcuma longa , has shown reliable anticancer function and low toxicity, thereby offering broad research prospects. Numerous studies have demonstrated the pharmacological mechanisms underlying the effectiveness of CUR against GIC, including the induction of apoptosis and autophagy, arrest of the cell cycle, inhibition of the epithelial–mesenchymal transition (EMT) processes, inhibition of cell invasion and migration, regulation of multiple signaling pathways, sensitization to chemotherapy and reversal of resistance to such treatments, and regulation of the tumor survival environment. It has been confirmed that CUR exerts its antitumor effects on GIC through these mechanisms in vitro and in vivo . Moreover, treatment with CUR is safe and tolerable. Newly discovered types of regulated cell death (RCD), such as pyroptosis, necroptosis, and ferroptosis, may provide a new direction for research on the efficacy of CUR against GIC. In this review, we discuss the recently found pharmacological mechanisms underlying the effects of CUR against GIC (gastric and colorectal cancers). The objective is to provide a reference for further research on treatments against GIC.
Cancer is the second most reason for huge mortality in human life which has attributed to a drastic drift in anticancer drug discovery and development. Small molecules as anticancer agents have contributed tremendously for the treatment of cancer however plants based natural products have the cardinal foundation for traditional medicine schemes and still offer relief to cancer patients. Medicinal plants are known for producing numerous bioactive secondary metabolites that have been used since antiquity due to their medicinal properties. Copious advantages of natural products over conventional anticancer drugs have expanded their use in the health care industry which has been witnessed by the extensive use of natural products in the treatment of multiple cancers. The pleiotropic effects of plant products on targets in multiple ways, phytochemicals are considered as suitable source candidates for anticancer drug design and development. In this review, we attempted to compile structural and functional attributes of natural products with an emphasis on their anticancer properties.
Curcumin [1,7‐bis(4‐hydroxy‐3‐methoxyphenyl) ‐1,6‐heptadiene‐3,5‐dione] is pharmacologically active polyphenol isolated from rhizome Curcumin longa L and is a versatile molecule known for its various biological properties including anti-inflammatory, antioxidant, antibacterial, including antibacterial, anticancer, arthritis, allergies and other various chronic diseases. In recent years this compound has attracted considerable attention due to multimodal effects. In this endeavor, novel curcumin derivatives have also been synthesized and tested against different models of human disease. The current chapter is a compilation of existing information from many recent studies utilizing curcumin in various disease conditions and the new drug delivery approach to tackle bioavailability issues have also been discussed. Further the ongoing clinical studies on curcumin in various disease conditions are also reviewed in this chapter.
Pluramycins is the general name of a family of natural products characterized by a common anthrapyranone framework, which is diversely substituted at the C2 and C5 positions and can exhibit a variety of deoxyaminosugars at C8 and C10. Their outstanding biological response towards many afflictions in humans has motivated an extensive study of structure-activity correlations, and at the same time, has encouraged efforts to develop improved total syntheses. The introduction of this review presents a general perspective of the topic, focusing on the structural features of these molecules. Subsequently, the following section summarizes the main range of biological activities exhibited by this group, particularly the antitumor and cytotoxic effects. Finally, the synthesis of these molecules is addressed on two fronts: biosynthetic and synthetic pathways. The last section described the most recent examples found in literature, thus completing the global panorama with which this issue is approached.
Cancer is a significant public health issue, as well as constituting one of the main causes of death with a drastic increase. Curcumin, an active ingredient of turmeric with yellow pigment properties, is a phytochemical that has been utilized in herbal medicine to treat a variety of diseases. Due to its antioxidant, anti-inflammatory, anti-fungal, anti-bacterial, anti-viral, and anti-angiogenic effects, it has been used in a wide range of therapeutic areas. Research findings on cancer of curcumin from cell models and human clinical trials have been reviewed. Potential mechanisms of curcumin, curcumin analogs, curcumin metabolites, on various cancers, are revised through their chemical, physical properties, bioavailability, physiological activities in this direction. Even at high doses, curcumin is known as well-tolerated and non-toxic. Laboratory studies have hitherto disclosed positive results, vis-à-vis the anti-cancer and chemo preventive properties viz. antioxidant, anti-inflammatory, anti-proliferative, anti-metastatic, anti-invasion activities, apoptosis, autophagy inducer curcumin holds. Curcumin has been corroborated to prevent carcinogenesis by modulating the cell cycle by binding molecular targets such as transcription factors, growth factors, inflammatory cytokines, specific genes, certain enzymes like kinases. Thence, arguably curcumin can make a difference in cancer treatment in the future, considering its advantages anent possible mechanisms, toxicity, and cost.
Obesity remains a pervasive health concern worldwide with concomitant comorbidities such as cardiovascular diseases, diabetes, inflammation, and other metabolic disorders. A wealth of data validates dietary and lifestyle modifications such as restricting caloric intake and increasing physical activity to slow the obesity development. Recently, the advent of phytochemicals such as curcumin, the active ingredient in turmeric, has attracted considerable research interest in tracking down their possible effects in protection against obesity and obesity-related comorbidities. According to the existing literature, curcumin may regulate lipid metabolism and suppress chronic inflammation interacting with white adipose tissue, which plays a central role in the complications associated with obesity. Curcumin also inhibits the differentiation of adipocyte and improves antioxidant properties. In the present review, we sought to deliberate the possible effects of curcumin in downregulating obesity and curtailing the adverse health effects of obesity.
Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in different aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efflux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also affect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs).
Nanoparticles have emerged as promising drug delivery systems for the treatment of several diseases. Novel cancer therapies have exploited these particles as alternative adjuvant therapies to overcome the traditional limitations of radio and chemotherapy. Curcumin is a natural bioactive compound found in turmeric, that has been reported to show anticancer activity against several types of tumors. Despite some biological limitations regarding its absorption in the human body, curcumin encapsulation in poly(lactic-co-glycolic acid) (PLGA), a non-toxic, biodegradable and biocompatible polymer, represents an effective strategy to deliver a drug to a tumor site. Furthermore, PLGA nanoparticles can be engineered with targeting moieties to reach specific cancer cells, thus enhancing the antitumor effects of curcumin. We herein aim to bring an up-to-date summary of the recently developed strategies for curcumin delivery to different types of cancer cells through encapsulation in PLGA nanoparticles, correlating their effects with those of curcumin on the biological capabilities acquired by cancer cells (cancer hallmarks). We discuss the targeting strategies proposed for advanced curcumin delivery and the respective improvements achieved for each cancer cell analyzed, in addition to exploring the encapsulation techniques employed. The conjugation of correct encapsulation techniques with tumor-oriented targeting design can result in curcumin-loaded PLGA nanoparticles that can successfully integrate the elaborate network of development of alternative cancer treatments along with traditional ones. Finally, the current challenges and future demands to launch these nanoparticles in oncology are comprehensively examined.
In recent years, immunotherapy has emerged as a novel antitumor strategy in addition to traditional surgery, radiotherapy and chemotherapy. It uniquely focuses on immune cells and immunomodulators in the tumor microenvironment and helps eliminate tumors at the root by rebuilding the immune system. Despite remarkable breakthroughs, cancer immunotherapy still faces many challenges: lack of predictable and prognostic biomarkers, adverse side effects, acquired treatment resistance, high costs, etc. Therefore, more efficacious and efficient, safer and cheaper antitumor immunomodulatory drugs have become an urgent requirement. For decades, plant-derived natural products obtained from land and sea have provided the most important source for the development of antitumor drugs. Currently, more attention is being paid to the discovery of potential cancer immunotherapy modulators from plant-derived natural products, such as polysaccharides, phenols, terpenoids, quinones and alkaloids. Some of these agents have outstanding advantages of multitargeting and low side effects and low cost compared to conventional immunotherapeutic agents. We intend to summarize the progress of comprehensive research on these plant-derived natural products and their derivatives and discuss their possible mechanisms in regulating the immune system and their efficacy as monotherapies or in combination with regular chemotherapeutic agents.
Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapyrepresent effective strategies for treatment. However, in some cases with high metastatic activityand high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods isinsufficient and results in treatment failure and reduced patient survival. CTCs are seen not onlyas an isolated phenomenon but also a key inherent part of the formation of metastasis and a keyfactor in cancer death. This review discusses the impact of NSCLC therapy strategies based on ameta-analysis of clinical studies. In addition, possible therapeutic strategies for repression whenstandard methods fail, such as the administration of low-toxicity natural anticancer agents targetingthese phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in thecontext of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis(mechanisms related to tumour-associated and -infiltrating cells, epithelial–mesenchymal transition,and migration of cancer cells).
The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.
Bitkisel ürünler insanlık tarihi boyunca çeşitli amaçlarla kullanılmıştır. Bu ürünlerin çoğu, ilaçların keşfi ve tasarımında yararlanılabilecek farmakolojik veya biyolojik aktiviteye sahiptir. Zerdeçal, zencefil ailesinin bir üyesi Kurkuma longa bitkisinden elde edilmiştir. Zerdeçal, Hint ayurvedik tıbbında ve Unani geleneksel tıbbında en az 2500 yıldır sindirim ve karaciğer hastalıkları, deri enfeksiyonları ve artrit tedavisinde kullanılmaktadır. İlk kez 1815'te Vogel ve Pelletier tarafından zerdeçaldan izole edilmiş olan kürküminin 1870'de saf ve kristal formu, 1910'da ise diferuloilmetan yapısı bulunmuştur. Zerdeçalın 100 gramında; 390 kcal, toplam 10 g yağ, 3 g doymuş yağ, 0 mg kolesterol, 0.2 g kalsiyum, 0.26 g fosfor, 10 mg sodyum, 2500 mg potasyum, 47.5 mg demir, 0.9 mg tiamin, 0.19 mg riboflavin, 4.8 mg niasin, 50 mg askorbik asit, toplam 69.9 g karbonhidrat, 21 g diyet lifi, 3 g şeker ve 8 g protein bulunmaktadır. Zerdeçaldaki ana biyoaktif bileşen olan kürkümin, antioksidan, anti-inflamatuar, anti-bakteriyel ve anti-aterosklerotik özelliklere sahiptir. Bu özellikleri zerdeçalı, Alzheimer, kanser, kardiyovasküler hastalıklar, diyabet, obezite ve depresyon gibi pek çok hastalığın tedavisinde ilgi çekici kılmıştır. Bu derlemede zerdeçalın genel sağlık üzerine etkilerinin irdelenmesi amaçlanmıştır.
Respiratory depression is the opioid adverse effect feared most by physicians. This may hinder adequate dosing in cancer pain. The study was conducted to examine the respiratory function of patients with advanced cancer receiving significant doses (>100 mg/24 h) of oral morphine.
Consecutive pain-free hospice inpatients with advanced cancer receiving high-dose immediate-release oral morphine were evaluated. A single assessment of respiratory rate (RR), arterial blood gas (ABG), and peak flow rate (PFR) was made at assumed morphine steady state. Venous blood was drawn for a trough morphine plasma level.
Of 31 patients who consented to examination, 20 completed the study assessment; 12 had chronic bronchitis. The median morphine dose was 30 mg 4-hourly (range 20 to 90 mg). Only one patient had evidence of ventilatory impairment.
Morphine does not commonly cause chronic ventilatory impairment when given in this way in this population even in the presence of pre-existing or concurrent respiratory disease. Oral morphine given repeatedly in individualized dosage is a safe and efficacious analgesic in the majority of those with advanced cancer.
Food allergy and chronic intestinal inflammation are common in western countries. The complex of antigen/IgE is taken up into the body from the gut lumen with the aid of epithelial cell-derived CD23 (low affinity IgE receptor II) that plays an important role in the pathogenesis of intestinal allergy. This study aimed to elucidate the role of mast cell on modulation of antigen/IgE complex transport across intestinal epithelial barrier.
Human intestinal epithelial cell line HT29 cell monolayer was used as a study platform. Transepithelial electric resistance (TER) and permeability to ovalbumin (OVA) were used as the markers of intestinal epithelial barrier function that were recorded in response to the stimulation of mast cell-derived chemical mediators.
Conditioned media from naïve mast cell line HMC-1 cells or monocyte cell line THP-1 cells significantly upregulated the expression of CD23 and increased the antigen transport across the epithelium. Treatment with stem cell factor (SCF), nerve growth factor (NGF), retinoic acid (RA) or dimethyl sulphoxide (DMSO) enhanced CD23 expression in HT29 cells. Conditioned media from SCF, NGF or RA-treated HMC-1 cells, and SCF, NGF, DMSO or RA-treated THP-1 cells enhanced immune complex transport via enhancing the expression of the CD23 in HT29 cells and the release of inflammatory mediator TNF-α. Nuclear factor kappa B inhibitor, tryptase and TNF-α inhibited the increase in CD23 in HT29 cells and prevents the enhancement of epithelial barrier permeability.
Mast cells play an important role in modulating the intestinal CD23 expression and the transport of antigen/IgE/CD23 complex across epithelial barrier. (Tu YH, Oluwole C, Struiksma S, Perdue MH, Yang PC. Mast cells modulate transport of CD23/IgE/antigen complex across human intestinal epithelial barrier.
Recent evidence suggests that antiangiogenic therapy is sensitive to p53 status in tumors, implicating a role for p53 in the
regulation of angiogenesis. Here we show that p53 transcriptionally activates the α(II) collagen prolyl-4-hydroxylase [α(II)PH]
gene, resulting in the extracellular release of antiangiogenic fragments of collagen type 4 and 18. Conditioned media from
cells ectopically expressing either p53 or α(II)PH selectively inhibited growth of primary human endothelial cells. When expressed
intracellularly or exogenously delivered, α(II)PH significantly inhibited tumor growth in mice. Our results reveal a genetic
and biochemical linkage between the p53 tumor suppressor pathway and the synthesis of antiangiogenic collagen fragments.
The Prognostic Inflammatory Nutritional Index (PINI) is a simple scoring system that has been used to evaluate nutritional status and prognosis in critically ill patients. The PINI has never been evaluated in advanced cancer. Fifty consecutive patients with advanced cancer, weight loss, and anorexia were studied. C-reactive protein (CRP), albumin, pre-albumin, interleukin-6 (IL-6), and alpha 1-acid glycoprotein (AAG) were evaluated. The individual values for AAG, CRP, and IL-6 were markedly elevated. In contrast to albumin and prealbumin, CRP levels were very high. The PINI was significantly elevated, and higher than reported in critically ill intensive care patients. Elevated IL-6 levels correlated with high PINI and CRP values. CRP, IL-6, and PINI should be considered in future research on nutritional status and prediction of prognosis in advanced cancer.
The prognostic effect of weight loss prior to chemotherapy was analyzedusing data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.
Much research has addressed the association between provider case volume and mortality. We systematically reviewed this association in 96 primary studies involving over one million patients with oesophageal, gastric, hepatic, pancreatic, colonic or rectal cancer, among whom over 70,000 deaths were recorded. Most studies addressed the relationship between hospital surgical case volume and short-term peri-operative mortality. Few studies have addressed the impact of surgeon case volume or evaluated long-term survival as an outcome. Common methodological limitations in estimating magnitude of a volume-related effect were failure to control for potential important confounders, post-hoc categorisation of provider volume and unit of analysis errors.
We found a large volume effect for most gastrointestinal cancers: with each doubling of hospital case volume the odds of peri-operative death decreased by 0.1 to 0.23. This effect was apparent for case volumes ranging from fewer than ten to several hundred per year, with no clear threshold levels. We calculated that between 10 and 50 patients per year, depending on cancer type, need to be moved from a ‘low volume’ hospital to a ‘high volume’ hospital in order to prevent one additional volume-associated peri-operative death. Despite these findings, a number of large studies found no apparent association between hospital volume and peri-operative mortality. The heterogeneity of results from individual studies calls into question the validity of case volume as a proxy for care quality, and leads us to conclude that more direct quality measures and the validity of their use to inform policy should be explored.
The authors systematically reviewed the association between provider case volume and mortality in 101 publications involving greater than 1 million patients with esophageal, gastric, hepatic, pancreatic, colon, or rectal cancer, of whom more than 70,000 died. The majority of studies addressed the relation between hospital surgical case volume and short-term perioperative mortality. Few studies addressed surgeon case volume or evaluated long-term survival outcomes. Common methodologic limitations were failure to control for potential confounders, post hoc categorization of provider volume, and unit of analysis errors. A significant volume effect was evident for the majority of gastrointestinal cancers; with each doubling of hospital case volume, the odds of perioperative death decreased by 0.1 to 0.23. The authors calculated that between 10 and 50 patients per year, depending on cancer type, needed to be moved from a “low-volume” hospital to a “high-volume” hospital to prevent 1 additional volume-associated perioperative death. Despite this, approximately one-third of all analyses did not find a significant volume effect on mortality. The heterogeneity of results from individual studies calls into question the validity of case volume as a proxy for care quality, and leads the authors to conclude that more direct quality measures and the validity of their use to inform policy should also be explored. CA Cancer J Clin 2009;59:192–211. © 2009 American Cancer Society.
Curcumin is a polyphenol derived from Curcuma longa. Over the last few years, a number of studies have provided evidence of its main pharmacological properties including chemosensitizing, radiosensitizing, wound healing activities, antimicrobial, antiviral, antifungical, immunomodulatory, antioxidant and anti-inflammatory. More recent data provide interesting insights into the effect of this compound on cancer chemoprevention and chemotherapy. In fact, preclinical studies have shown its ability to inhibit carcinogenesis in various types of cancer including colorectal cancer (CRC). Curcumin has the capacity of interact with multiple molecular targets affecting the multistep process of carcinogenesis. Also, curcumin is able to arrest the cell cycle, to inhibit the inflammatory response and the oxidative stress and to induce apoptosis in cancer cells. Likewise, it has been shown to possess marked antiangiogenic properties. Furthermore, curcumin potentiates the growth inhibitory effect of cyclo-oxygenase (COX)-2 inhibitors and traditional chemotherapy agents implicating another promising therapy regimen in the future treatment of CRC. However, its clinical advance has been hindered by its short biological half-life and low bioavailability after oral administration. This review is intended to provide the reader an update of the bioavailability and pharmacokinetics of curcumin and describes the recently identified molecular pathways responsible of its anticancer potential in CRC.
Paramount to the maintenance of normal tissue homeostasis is the induction of programmed cell death, otherwise known as apoptosis. Several disease states, including cancer, are characterized by an inability to remove unwanted cells due to a failure to commit to apoptosis. What is more, apoptosis is the central functional response behind many agents utilized in the treatment of cancer. Many of these antitumorigenic agents rely on the activation of the tumor suppressor p53. As the physiological "guardian of the genome," p53's normal function is to sense stressed or damaged cells and arrest proliferation, allowing time for cellular repair. However, if the damage is excessive, cells are removed prior to the onset of malignancy through apoptosis. Current chemotherapeutic strategies manipulate this property by damaging cells and turning on p53's transcriptional function, which consequently upregulates the expression of proapoptotic proteins such as Puma. We have also demonstrated that Puma is capable of inducing apoptosis independent of p53. In this regard, defects in the apoptotic machinery or in p53 function itself lead to a resistant phenotype that in cancer results in chemotherapeutic failure, and more often than not, poor prognosis. This chapter describes protocols for the determination of p53-dependent and -independent apoptosis utilizing primary cells from genetically altered mice.
The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of colon cancer. This overview of clinical studies describes the effects of administering the targeted agents bevacizumab, cetuximab, and panitumumab, also known as monoclonal antibodies, to treat metastatic colorectal cancer (mCRC) patients. All three targeted agents have been approved for use by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Bevacizumab has been shown to extend survival when used in combination with irinotecan and 5-fluorouracil-based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil-based chemotherapy overcomes irinotecan resistance. Cetuximab and panitumumab are both efficacious among refractory mCRC patients with wild-type KRAS tumors. Other targeted agents, for example, the tyrosine kinase inhibitors erlotinib, gefitinib, sunitinib, and vatalanib (PTK787/ZK 222584), are currently in various stages of clinical development.
Many data support the beneficial effect of n-3 polyunsaturated fatty acids (PUFAs) as chemopreventive and chemotherapeutic agents in the treatment of several chronic pathologies including cancer. Different molecular mechanisms have been proposed to explain their effects, including alterations in arachidonic acid oxidative metabolism and metabolic conversion of n-3 PUFAs to novel discovered bioactive derivatives; modification of oxidative stress; changes in cell membrane fluidity and structure and altered metabolism and function of membrane proteins. Considerable knowledge has been recently gathered on the possible beneficial effects of n-3 PUFAs administered in combination with different antineoplastic drugs and radiotherapy against melanoma, leukemia, neuroblastoma, and colon, breast, prostate, and lung cancer. The efficacy of these combinations has been demonstrated both in vivo and in vitro, and clinical trials have also been conducted. The aim of this review is to analyze all the n-3 PUFA combinations investigated so far, their efficacy, and the possible molecular mechanisms involved. It would be highly auspicable that the detailed analysis of the literature in this field could further support the common use of n-3 PUFAs in combination with other chemopreventive agents and warrant more clinical investigations designed to test the effectiveness of n-3 PUFA treatments coupled with conventional antineoplastic therapies.
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), is extracted from the plant Curcuma longa. It has cytotoxic effects and induces apoptosis in many human cancer cells but the molecular mechanisms are not fully understood. In the present study, we evaluated the effects of curcumin on human breast cancer MDA-MB-231 cells. The cytotoxic effects of curcumin on MDA-MB-231 cells were measured by MTT assay. The percentages of cell cycle were determined by flow cytometry. The protein expressions of p21, 53, Bax and Bcl-2 were examined by Western blotting. The results show that curcumin inhibits the proliferation of MDA-MB-231 cells and induces G2/M arrest in a dose-dependent manner. Curcumin increased the protein expressions of p21 and Bax, but decreased the protein expression of p53 and Bcl-2 in MDA-MB-231 cells. Our results show that one molecular mechanism of curcumin inhibits the proliferation of MDA-MB-231 cells either through up-regulating p21 expression and then inducing apoptosis, or through up-regulating the Bax to Bcl-2 ratio and then inducing apoptosis. Our results also show that curcumin inhibits the migratory activity of MDA-MB-231 cells through down-regulating the protein expression of NF-kappaBp65. Accordingly, the therapeutic potential of curcumin for breast cancer deserves further study.
Cancer cachexia-associated weight loss is poorly understood; energetically demanding tissues (eg, organ and tumor mass) and resting energy expenditure (REE) are reported to increase with advanced cancer.
The objective was to quantify the potential contribution of increasing masses of energetically demanding tissues to REE with colorectal cancer cachexia progression.
A longitudinal computed tomography (CT) image review was performed to quantify organ size (liver, including metastases, and spleen) and peripheral tissues (skeletal muscle and adipose tissue) during colorectal cancer cachexia progression (n = 34). Body composition was prospectively evaluated by CT and dual-energy X-ray absorptiometry, and REE was determined by indirect calorimetry in advanced colorectal cancer patients (n = 18).
Eleven months from death, the liver (2.3 +/- 0.7 kg) and spleen (0.32 +/- 0.2 kg) were larger than reference values. One month from death, liver weight increased to 3.0 +/- 1.5 kg (P = 0.010), spleen showed a trend to increase (P = 0.077), and concurrent losses of muscle (4.2 kg) and fat (3.5 kg) (P < 0.05) were observed. The estimated percentage of fat-free mass (FFM) occupied by the liver increased from 4.5% to 7.0% (P < 0.001). The most rapid loss of peripheral tissues and liver and metastases gain occurred within 3 mo of death. A positive linear relation existed between liver mass and measured whole-body REE (r(2) = 0.35, P = 0.010); because liver accounted for a larger percentage of FFM, measured REE . kg FFM(-1) . d(-1) increased (r(2) = 0.35, P = 0.010).
Increases in mass and in the proportion of high metabolic rate tissues, including liver and tumor, represented a cumulative incremental REE of approximately 17,700 kcal during the last 3 mo of life and may contribute substantially to cachexia-associated weight loss.
The infection with Friend murine leukemia virus (FMuLv) is being used as a retrovirus infection model for searching the potential anti-viral medicinal preparations or establishing new treatment strategies. In the present study we have evaluated the inhibitory effect of three non-toxic antiviral natural compounds namely berberine, curcumin or picroliv against FMuLv induced erythroleukemia in BALB/c mice. To understand the effect of these compounds in the initiation and progression of leukemia we did a series of analysis, which include hematological and biochemical parameters, histopathological evaluations of the liver and the spleen and expression analysis of selected genes such as Bcl-2, p53, p45NFE2, Raf-1, Erk-1, IFNgamma receptor and erythropoietin in spleen. The treatment with berberine, curcumin or picroliv were found to (a) elevate the life span of leukemia harboring animals by more than 60 days; (b) decreased the anemic condition which was highly prevalent in FMuLv alone treated group; (c) histopathological evaluations showed that the compounds tested here inhibited the massive leukemic cell infiltrations to sinusoidal spaces in spleen; (d) decrease the expression of Bcl-2, Raf-1, Erk-1 IFNgamma receptor and erythropoietin; (e) induce the expression of p53. Overall, our results suggest that berberine, curcumin and picroliv were able to suppress the progression of leukemia induced by FMuLv and further support their chemopreventive potential against virally induced cancers.
Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.
Curcumin, a natural compound derived from tumeric, has been shown to induce apoptosis in the leukemic cell line K562 and other cancer cell lines. However, it is unknown whether curcumin also has an inhibitory effect on BCR-ABL-expressing B-lymphoid cells. We tested whether curcumin has an inhibitory effect on BCR-ABL B-cell acute lymphoblastic leukemia (B-ALL) in vitro and in vivo.
Pre-B cells isolated from B6 mice expressing wild-type BCR-ABL (B6p210) and T315I mutant (B6T315I) were cultured in serial concentration of curcumin. Cultured cells were analyzed by automated cell counter, flow cytometry, western blotting, and transcription factor arrays. B-ALL was induced by transplantation of MSCV-GFP-p210 transduced donor marrow in lethally irradiated Balb/c mice. Diseased mice were treated with placebo or curcumin until death of the mice. Diseased mice were analyzed by flow cytometric and histopathological analyses.
Curcumin inhibited the proliferation of B6p210 and B6T315I cells at concentration as low as 10 muM and induced apoptosis of the cells at concentrations of 30 muM. Using western blots and transcription factors arrays, we showed that curcumin decreased NF-kappaB levels and increased p53 levels. Curcumin decreased c-Abl levels in cells expressing the wild, but not the mutant, BCR-ABL oncogene. Curcumin treatment resulted in a statistically significant improved survival in diseased mice along with decreasing white blood and GFP cell counts.
Curcumin is effective against leukemic cells expressing p210 BCR-ABL and T315I BCR-ABL and holds promise in treating BCR-ABL-induced B-ALL.
The present study aims to access the effects of sophora alkaloids on the production of pro-inflammatory cytokines and evaluate their therapeutic efficiency on cachexia. The comparative study showed that all sophora alkaloids tested here, including matrine, oxymatrine, sophocarpine, sophoramine, and sophoridine, inhibited TNF-alpha and IL-6 production in both RAW264.7 cells and murine primary macrophages, and sophocarpine showed the most potent inhibitory effect among them. Quantification of TNF-alpha and IL-6 mRNA in RAW264.7 cells by real-time RT-PCR revealed that both sophocarpine and matrine suppressed TNF-alpha and IL-6 expression and sophocarpine has stronger suppressing potency than matrine. Inoculation (s.c.) of colon26 adenocarcinoma cells into BALB/c mice induced cachexia, as evidenced by progressive weight loss, reduction in food intake, wasting of gastrocnemius muscle and epididymal fat, and increase in serum levels of TNF-alpha and IL-6. Administration of 50 mg/kg/d sophocarpine or matrine for 5 days from the onset of cachexia did not inhibit the tumor growth but resulted in attenuation of cachexia symptoms. Furthermore, sophocarpine and matrine decreased the serum levels of TNF-alpha and IL-6, and sophocarpine showed a better therapeutic effect than matrine. These results suggest that sophocarpine and matrine exert anti-cachectic effects probably through inhibition of TNF-alpha and IL-6.
The prognostic effect of weight loss prior to chemotherapy was analyzed using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.
During the past 20 years, the flowering plant Arabidopsis thaliana has been adopted as a model organism by thousands of biologists. This community has developed important tools, resources and experimental approaches that have greatly stimulated plant biological research. Here, we review some of the key events that led to the uptake of Arabidopsis as a model plant and to the growth of the Arabidopsis community.
Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. Although this metabolic defect has been known since cancer was first studied, it is only recently that major advances have been made in the identification of catabolic factors that act to destroy host tissues during the cachectic process. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.
The development of cancer cachexia is perhaps the most common manifestation of advanced malignant diseases and has been recognized as a poor prognostic sign. The abnormalities associated with the condition include progressive weight loss, anorexia, asthenia, and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and always implies a poor prognosis. Currently there is no established mechanism for cancer cachexia, but the severe metabolic disturbances and marked alterations in carbohydrate, lipid, and protein metabolism in the host finally lead to an increased energy deficiency. Weight loss, the key feature of cachexia, is due to a reduction of food intake, an increase in energy expenditure, or a combination of the two. A variety of changes in nutrient metabolism have been described in patients with cancer cachexia. Patients frequently exhibit a relative glucose intolerance and insulin resistance with increased activity of the Cori cycle. The cancer-bearing state affects protein synthesis and breakdown in different tissues of the body in a different manner. An acute-phase protein response can be presented in a significant proportion of patients with cancer with disease progression. A variety of proinflammatory cytokines appears to play a role in aspects of cachexia and a complex network of cytokines in combination with other factors might be involved. Aside from potential humoral mediators of cachexia, tumor-derived biologically active molecules have been reported recently.
Food allergy accounts for significant morbidity. The etiology and immune mechanisms of food allergy, however, have remained poorly understood. In this study, we aimed to determine the role of T-cell immunoglobulin-domain and mucin-domain (TIM)-4, a recently identified member of cell surface molecules, in the pathogenesis of intestinal allergy in a murine model.
We report that TIM-4 as well as costimulatory molecules were up-regulated in intestinal mucosal dendritic cells by in vitro or in vivo exposure to Staphylococcus enterotoxin B (SEB). SEB-conditioned intestinal dendritic cells loaded with a food macromolecule ovalbumin (OVA) induced potent OVA-specific T-helper (Th)2 lymphocyte responses in vitro and such Th2 responses were inhibited completely by TIM-4 blockade.
In vivo exposure to both SEB and OVA resulted in OVA-specific Th2 differentiation and intestinal allergic responses including increased serum immunoglobulin E and Th2 cytokine levels, activation of OVA-specific Th2 cells detected both ex vivo and in situ, and mast cell degranulation. Of importance, in vivo abrogation of TIM-4 or its cognate ligand TIM-1 by using a polyclonal antibody remarkably dampened Th2 differentiation and intestinal allergy.
Our study thus identifies TIM-4 as a novel molecule critically required for the development of intestinal allergy.
Cancer cachexia is associated with weight loss, poor nutritional status, and systemic inflammation. Accurate nutritional support for patients is calculated on resting energy expenditure (REE) measurement or prediction. The present study evaluated the agreement between measured and predicted REE (mREE and pREE, respectively) and the influence of acute phase response (APR) on REE.
Thirty-six patients with cancer were divided into weight-stable (WS; weight loss <2%) and weight-losing (WL; weight loss >5%) patients. Measured REE was measured by indirect calorimetry and adjusted for fat-free mass (FFM). The Bland-Altman approach was used to assess the agreement between mREE and pREE from the Harris-Benedict equations (HBE). Blood levels of C-reactive protein were assessed.
There was no difference in mREE between groups (WS 1677 +/- 273, WL 1521 +/- 305) even when mREE was adjusted for FFM (WS 1609 +/- 53, WL 1589 +/- 53). In WL patients, FFM-adjusted REE correlated with blood C-reactive protein levels (r = 0.471, P = 0.048). HBEs tend to underestimate REE in both groups.
WL and WS patients with cancer had similar REEs but were different in terms of APR. APR could contribute to weight loss through enhancing REE. In a clinical context, HBE was in poor agreement with mREE in both groups.
Although traditional medicines have been used for thousands of years, for most such medicines neither the active component nor their molecular targets have been very well identified. Curcumin, a yellow component of turmeric or curry powder, however, is an exception. Although inhibitors of cyclooxygenase-2, HER2, tumor necrosis factor, EGFR, Bcr-abl, proteosome, and vascular endothelial cell growth factor have been approved for human use by the United States Food and Drug Administration (FDA), curcumin as a single agent can down-regulate all these targets. Curcumin can also activate apoptosis, down-regulate cell survival gene products, and up-regulate p53, p21, and p27. Although curcumin is poorly absorbed after ingestion, multiple studies have suggested that even low levels of physiologically achievable concentrations of curcumin may be sufficient for its chemopreventive and chemotherapeutic activity. Thus, curcumin regulates multiple targets (multitargeted therapy), which is needed for treatment of most diseases, and it is inexpensive and has been found to be safe in human clinical trials. The present article reviews the key molecular mechanisms of curcumin action and compares this to some of the single-targeted therapies currently available for human cancer.
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New mech-anisms and therapeutic potential of curcumin for colorectal can-cer
- Villegas I S Sá-Fidalgo
- Alarcó
Villegas I, Sá-Fidalgo S, Alarcó ?, de la Lastra C. New mech-anisms and therapeutic potential of curcumin for colorectal can-cer. Mol Nutr Food Res 2008;52(9):1040–1061.