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We would like to thank the Clinical Research Development Unit of Sina Educational, Research and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran for their assistance in this research. This work was supported by Tabriz University of Medical Sciences of Iran.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Department of Pharmacognosy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran. Department of Molecular Medicine, Faculty of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.

Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Agro Produce Processing Division, ICAR—Central Institute of Agricultural Engineering, Bhopal, , India. Chemical and Biochemical Processing Division, ICAR—Central Institute for Research on Cotton Technology, Mumbai, , India.

Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Clinical Research Development Unit of Sina Educational, Research, and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Scientific Production and Technical Center Zhalyn, А20Х3F6, Almaty, Kazakhstan. Facultad de Medicina, Universidad del Azuay, , Cuenca, Ecuador.

Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, , Craiova, Romania. Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China.

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Abstract Over the past few years, the cancer-related disease has had a high mortality rate and incidence worldwide, despite clinical advances in cancer treatment.

Introduction Cancer is a set of diseases in which cells develop abnormally and have the ability to invade and spread metastasize to other parts of the body [ 1 , 2 ]. The p53, NF-ĸB, and apoptotic pathways In human CRC cell lines obtained from patients with microsatellite instability MSI , quercetin stimulated 5-fluorouracil-induced apoptosis in a pdependent way [ 75 ].

Table 1 The role of quercetin in various cancers mediated by signalling pathways—evidence from preclinical studies Full size table. Full size image. Epigenetic modulation by quercetin Regulation of miRNAs in different cancer types: effects on cancer cell progression and proliferation Part of the quercetin anticancer effect is exerted by regulating the expression of miRNAs Additional file 1 and the interaction between quercetin and miRs is an important subject that has been investigated in many studies Fig.

Quercetin as bioactive molecule in cancer Plants are important sources for the treatment of cancers because they contain secondary plant metabolites [ , , ]. Structural activity relationship of quercetin with anticancer mechanism Quercetin is a flavonoid and chemically it is a phenyl-substituted chromone composed of a basic skeleton of fifteen carbon atoms, composed of a chromium nucleus formed by the benzo ring A and the heterocyclic ring C, and in the aromatic ring B has a phenyl substitution [ ].

Therapeutic perspectives Despite numerous advances in cancer treatment, it is still a life-threatening disease [ , , ]. Concluding remarks The plant derivative is an appealing source of alternative anti-tumor drugs.

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Furthermore, for apoptosis evaluation in the animals, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling TUNEL assay was performed. The study protocol was approved by the Ethics Committee of Zabol University of Medical Sciences.

All experimental procedures conformed to the declaration of Helsinki and were conducted in accordance with recent legislation of National Institutes of Health guide for the care and use of laboratory animals.

Implanted tumor tissues were collected and apoptosis was detected using TUNEL assay. Based on the instructions of the manufacturer Roche Diagnostics, Basel, Switzerland , paraformaldehyde-fixed blocks were embedded in paraffin, cut into 4-µm thick slices, and incubated with TUNEL reaction mixture containing TdT and fluorescein-dUTP.

Prior to incubation of the slices with TUNEL mixture, their permeability was enhanced by proteinase solution. The TUNEL signal was then detected by an anti-fluorescein antibody conjugated with alkaline phosphatase in situ Cell Death Detection kit; Roche; Sigma , a reporter enzyme, which catalytically generates a colored product.

Three slides from each block and four slide fields were evaluated for the percentage of apoptotic cells. Statistical analysis was performed using the Student's t-test. Data are presented as the means ± standard deviation of 3 independent treatments. MTT assay was used to evaluate the viability of all 9 cancer cell lines following 24, 48 and 72 h of treatment with quercetin at 10, 20, 40, 80 and µM Table I.

All utilized concentrations of quercetin were inhibitory with the exception of the PC3 and CHO cells where at the 24 h time point, no inhibition was evident even at the highest concentration µΜ as presented in Table II.

Furthermore, MTT assay revealed that the inhibitory effect of each concentration of quercetin on the viability of all cancer cell lines was enhanced by an increase in the incubation time. In addition, we calculated the IC 50 values as previously described by Entezari Heravi et al Therefore, the inhibitory effect of quercetin on the growth of utilized cancer cell lines was dose- and time-dependent, as demonstrated by the obtained IC 50 values of quercetin Table II.

It is noteworthy, based on our cancer cell line panel Table II , that we selected cell lines of lower and higher sensitivity to quercetin. Data obtained from MTT assay on the cell viability of different cell lines treated with quercetin 10, 20, 40, 80 and µM for 24, 48 and 72 h.

IC50 values in µM for the studied cell lines following treatment with various concentrations of quercetin 10, 20, 40, 80, µM for 24, 48 and 72 h. In continuation, we examined the apoptotic rate in a panel of 4 cell lines of high and low sensitivity to quercetin i. Our results revealed that quercetin initiated the apoptotic process in these cells in a dose-dependent manner Fig.

PI, propidium iodide. Early apoptotic cells are Annexin V-positive and PI-negative lower right quadrant. In continuation, we evaluated the in vivo effect of quercetin on CT and MCF-7 tumors; these cells lines exhibited a relatively lower sensitivity to quercetin in in vitro experiments Table II.

At the end of the experiment 36 days following treatment , all surviving animals were sacrificed, and tumors from all animals were dissected and the poly-D-lysine-coated coverslips for TUNEL assay were positioned.

In spite of many advances in cancer therapy, cancer is still one of the major causes of mortality worldwide. Natural products, particularly flavones found in the human diet, have been found to exert anti-proliferative and apoptosis-promoting effects against cancer cells 60 , The current study demonstrated that quercetin induces the apoptosis of various cancer cell lines.

Furthermore, a significant increase in the survival rate and a significant reduction in tumor volume was observed in tumor-bearing animals treated with quercetin. Previous studies have shown that grape stem extracts have an ability to inhibit the growth of colon HT29 , breast MCF-7 , renal Caki-1 and thyroid K1 cancer cell lines 62 , These extracts are rich in flavonols, particularly quercetin and rutin Importantly, quercetin was found to be in both aglycon and glycoside forms The inhibitory effect of quercetin on cancer cell growth is attributed to the inhibition of survival signaling proteins, such as protein kinase C PKC-α and the activation of death signals, such as PKC-δ Moreover, grape stem extracts seem to present an anti-angiogenic potential evident by VEGF downregulation Furthermore, quercetin induces pro-apoptotic effects via different mechanisms involving antioxidant effects and the suppression of p53 gene and BCL-2 protein The suppression of BCL-2 gene transcription diminishes the inhibitory effects on BAD protein in the mitochondria, which is considered as the initiator of apoptosis for the intrinsic pathway The role of quercetin in apoptosis mediated by p53 has been studied in many cancer cell lines.

When p53 is inhibited, cells become more susceptible toward cytotoxicity induced by quercetin Apart from cell cycle regulation and the induction of apoptosis, p53 acts as a modulator of intracellular levels of ROS.

In this regard, p53 exerts antioxidant effects in cells with no or low stress through the regulation of genes involved in such activity, which comprises microsomal GSH transferase homolog PIG12 69 , aldehyde dehydrogenase 4 family member A1 ALDH4A1 70 , Gpx1, manganese superoxide dismutase SOD2 71 and catalase Some studies, however, have suggested that the effect of quercetin may be independent of p Although apoptotic cell death caused by DNA damage is often mediated by p53, there are other proteins, such as p63 and p73, which may be involved in this mechanism Chien et al demonstrated that quercetin-induced apoptotic cell death was accompanied by a decrease in p53 expression in breast cancer cells Additionally, quercetin inhibited the metabolic activity and induced cell death by apoptosis, followed by an increase in BAX expression with a concomitant decrease in the expression of anti-apoptotic proteins.

The flavonoid has structural homology to the PI3K inhibitor, LY LY and as expected, the phytochemical was found to inhibit the PI3K-Akt pathway in a similar manner to the inhibition elicited by LY in the breast cancer cell lines, HCC and T47D Quercetin exerts anticancer effects through the cell death domain mechanism at the cell surface Quercetin activated the cell death domain which leads to FAS and FADD activation, and the induction of cell death in a cancer cell line via activation of caspase 8 The expression of heat shock proteins HSPs in almost all forms of cancer is elevated Badziul et al showed that quercetin decreased the transcription and translation of HSP27 and 72 in the T98G cell line HSPs are involved in cell proliferation and the inhibition of their production leads to cell apoptosis This is well in accordance with our study, as we demonstrated that apoptosis was induced in quercetin-treated cancer cell lines.

HSP27 has been reported to promote the development of leukemia by protecting tumor cells from apoptosis through various mechanisms. Another study investigated the effects of small hairpin sh RNA-mediated HSP27 knockdown on the anticancer effects of quercetin in U human leukemia cells.

Moreover, this combined treatment significantly suppressed the infiltration of tumor cells and the expression of the angiogenesis-associated proteins, hypoxia-inducible factor 1α HIF1α and vascular endothelial growth factor VEGF. In comparison with shHSP27 or quercetin separately, shHSP27 and quercetin together, notably decreased the expression of cyclin D1, and thus the cell cycle was arrested at the G1 phase The anticancer effects of quercetin have been confirmed in many studies 36 , 42 , Specifically, in vitro and in vivo studies have suggested that quercetin possesses anticancer activity against different tumors; e.

colon, lung, breast and prostate cancer 78 , 80 — An in vivo examination of the effects of quercetin in mice bearing CT tumors was performed for the first time in this study, at least to the best of our knowledge.

The results revealed that quercetin significantly reduced the tumor volume and increased animal survival. Previous studies have provided evidence for the anticancer effects of quercetin on breast and prostate cancers in vivo 86 , 87 , an observation which was verified in the current study using the MCF-7 breast cancer in vivo model.

Importantly, quercetin can exert tumor suppressive effects by interfering with the cell cycle. The molecular targets of this flavonoid include p27, topoisomerase II, p21 and cyclin B 88 , In breast cancer cell lines, a low dose of quercetin has been shown to induce mild DNA damage and Chk2 activation, which is the main regulator of p21 expression Moreover, quercetin can inhibit the recruitment of NF-Y, a key transcription factor, which binds to the cyclin B1 gene promoter and leads to transcriptional cessation.

In the human hepatoma cell line HepG2 , quercetin upregulated p21, p27 and p53, and consequently the cells were arrested at the G1 phase Furthermore, quercetin has been shown to inhibit NF-κB-evoked pathways of cell survival and reduce pro-inflammatory cytokine expression that finally leads to cancer formation Notably, quercetin inhibits the production of tumor necrosis factor TNF -α, a major pro-inflammatory molecule involved in chronic inflammatory diseases, which may develop into tumors.

The quercetin-induced suppression of TNF-α results in the stimulation of anti-inflammatory cytokines through the inhibition of NF-κB activation TNF-α is a major regulator of the cellular release of other chemokines, cytokines and other inflammatory mediators, and thus can be considered as a potential target for the treatment of inflammatory diseases and inflammation-driven cancer.

In the current study, quercetin was able to suppress tumor growth and improve animal survival independent of its action on the induction of apoptosis. Quercetin seems to play an inhibitory role in angiogenesis in human prostate tumor growth. A recent study using an animal model, indicated that low doses of quercetin inhibited the following angiogenic stages: proliferation and migration, as well as the invasion and tube formation of endothelial cells.

Protein expression analysis of prostate cancer cells treated with quercetin revealed the inhibition of the VEGF-induced phosphorylation of VEGFR-2 and its downstream targets, such as mTOR, Akt, and ribosomal S6 kinase Thus, quercetin can decrease tumor volume and increase animal survival rate following systemic administration, a finding which is consistent with the results of the present study.

The oral administration of quercetin is recommended for cancer prevention. In addition, in vitro studies have proved its potency in inhibiting the proliferation of colon cancer cells of different lineages 97 , However, in a phase-1 clinical study performed at the University of Birmingham for the evaluation of the non-toxic and anticancer efficacy of quercetin in terminally ill cancer patients, no patient achieved conventional radiological response according to the WHO criteria, despite favorable indications of its anticancer activity In conclusion, our results demonstrate that quercetin inhibits the growth of a panel of 9 cancer cell lines with various IC 50 values.

Cell growth inhibition was attributed to the induction of apoptosis, evident in the CT, PC, LNCaP and PC-3 cancer cell lines.

Furthermore, our results demonstrated that quercetin reduced CT and MCF-7 tumor volume in a mouse model and increased animal survival; however, we did not verify increased in situ apoptosis in the induced tumors.

The current study results strongly suggest that quercetin has potential for therapeutic application in neoplasia; however, further studies are required to confirm these findings. Schnekenburger M, Dicato M and Diederich M: Plant-derived epigenetic modulators for cancer treatment and prevention.

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Cancer Cell International volume 22Article number: Cite this antj-cancer. Metrics details. Over the past few years, the cancer-related Maximizing performance through proper nutrition prpoerties had a high mortality rate and incidence worldwide, despite clinical advances in cancer treatment. The drugs used for cancer therapy, have high side effects in addition to the high cost. Subsequently, to reduce these side effects, many studies have suggested the use of natural bioactive compounds. Properfies you for visiting an. You are using Body fat percentage and disease risk browser version with limited support for CSS. To obtain anti-cance best experience, we Self-care initiatives in diabetes management you use a more up to Quercetin and anti-cancer properties browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Naturally occurring compounds are considered as attractive candidates for cancer treatment and prevention. Quercetin and ellagic acid are naturally occurring flavonoids abundantly seen in several fruits and vegetables. In the present study, we evaluate and compare antitumor efficacies of quercetin and ellagic acid in animal models and cancer cell lines in a comprehensive manner.