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1.
Health benefits of garlic and other Allium vegetables (e.g., onions), such as lipid lowering and anticancer effects, are credited to metabolic byproducts, including diallyl trisulfide (DATS). Evidence for anticancer effects of garlic derives from both population-based case-control studies, and clinical and laboratory investigations using purified garlic constituents such as DATS. Studies have shown that DATS can offer protection against chemically-induced neoplasia as well as oncogene-driven spontaneous cancer development in experimental rodents. Mechanisms underlying cancer chemopreventive effects of DATS are not completely understood, but known pharmacological responses to this natural product include alteration in carcinogen-metabolizing enzymes, cell cycle arrest, induction of apoptotic cell death, suppression of oncogenic signal transduction pathways, and inhibition of neoangiogenesis. This article reviews mechanisms and targets of cancer chemoprevention by DATS.  相似文献   

2.
Coumarins and coumarin derivatives as well as diallyl polysulfides are well known as anticancer drugs. In order to find new drugs with anticancer activities, we combined coumarins with polysulfides in the form of di-coumarin polysulfides. These novel compounds were tested in the HCT116 colorectal cancer cell line. It turned out that they reduced cell viability of cancer cells in a time and concentration dependent manner. Cells tested with these coumarin polysulfides accumulate in the G(2)/M phase of the cell cycle and finally they go into apoptosis. A decrease in bcl-2 level, and increase in the level of bax, cytochrome c release into the cytosol, cleavage of caspase 3/7and PARP suggested that coumarin polysulfides induced the intrinsic pathway of apoptosis. Comparison of these new coumarin compounds with the well known diallyl polysulfides revealed that the coumarin disulfides were more active than the corresponding diallyl disulfides. The activities of the coumarin tetrasulfides and the corresponding diallyl tetrasulfides are similar. The novel coumarin compounds regulated the phosphatase activity of the cell cycle regulating cdc25 family members, indicating that these phosphatases are implicated in the induction of cell cycle arrest and possibly in apoptosis induction as well. In addition, coumarin polysulfides also down-regulated the level of cdc25C, which also contributed to the arrest in the G(2)-phase of the cell cycle.  相似文献   

3.
Zhang Y 《Mutation research》2004,555(1-2):173-190
Numerous studies in rodents have documented the cancer-preventive activity of a significant number of isothiocyanates (ITCs), the majority of which occur in plants, especially in cruciferous vegetables. Dietary ITCs may play an important role in the prevention of human cancers. Several recent epidemiological studies have already shown that dietary consumption of ITCs inversely correlates with the risk of developing lung, breast and colon cancers. ITCs are principally metabolized through the mercapturic acid pathway in vivo, giving rise to N-acetylcysteine conjugates, which are excreted in the urine. Analytical methods have been developed to allow detection of ITCs and their metabolites formed in the mercapturic acid pathway. Studies show that total urinary level of ITC equivalent is an excellent biomarker of human exposure to ITCs. Moreover, these methods also have made it possible to learn the bioavailability of ITCs from cruciferous vegetables. ITCs possess multiple anticarcinogenic mechanisms, including inhibition of carcinogen-activating enzymes, induction of carcinogen-detoxifying enzymes, increase of apoptosis, arrest of cell cycle progression, as well as several other mechanisms that are not yet fully described. These mechanisms, which are discussed in detail in this review, illustrate the remarkable ability of ITCs to inhibit cancer development-effective against both developing and developed cancer cells.  相似文献   

4.
Research over the last three decades has provided convincing evidence to support the premise that diets rich in fruits and vegetables may be protective against the risk of different types of cancers. Initial evidence for protective effect of fruits and vegetables against cancer risk came from population-based case-control studies, which prompted intense research aimed at (a) identification of bioactive component(s) responsible for the anticancer effects of fruits and vegetables, (b) elucidation of the mechanisms by which bioactive food components may prevent cancer, and (c) determination of their efficacy for prevention of cancer in animal models. The bioactive components responsible for cancer chemopreventive effects of various edible plants have now been identified. For instance, anticancer effect of Allium vegetables including garlic is attributed to organosulfur compounds (e.g., diallyl trisulfide). Interestingly, unlike cancer chemotherapy drugs, many bioactive food components selectively target cancer cells. Molecular basis for selectivity of anticancer bioactive food components towards cancer cells remains elusive, but these agents appear promiscuous and target multiple signal transduction pathways to inhibit cancer cell growth in vitro and in vivo. Despite convincing observational and experimental evidence, however, limited effort has been directed towards clinical investigations to determine efficacy of bioactive food components for prevention of human cancers. This article reviews current knowledge on cancer chemopreventive effects of a few highly promising dietary constituents, including garlic-derived organosulfides, berry compounds, and cruciferous vegetable-derived isothiocyanates, and serves to illustrate complexity of the signal transduction mechanisms in cancer chemoprevention by these promising bioactive food components.  相似文献   

5.
Wang K  Liu R  Li J  Mao J  Lei Y  Wu J  Zeng J  Zhang T  Wu H  Chen L  Huang C  Wei Y 《Autophagy》2011,7(9):966-978
Quercetin, a dietary antioxidant present in fruits and vegetables, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing cell cycle arrest and promoting apoptotic cell death. In this study, we examined the biological activities of quercetin against gastric cancer. Our studies demonstrated that exposure of gastric cancer cells AGS and MKN28 to quercetin resulted in pronounced pro-apoptotic effect through activating the mitochondria pathway. Meanwhile, treatment with quercetin induced appearance of autophagic vacuoles, formation of acidic vesicular organelles (AVOs), conversion of LC3-I to LC3-II, recruitment of LC3-II to the autophagosomes as well as activation of autophagy genes, suggesting that quercetin initiates the autophagic progression in gastric cancer cells. Furthermore, either administration of autophagic inhibitor chloroquine or selective ablation of atg5 or beclin 1 using small interfering RNA (siRNA) could augment quercetin-induced apoptotic cell death, suggesting that autophagy plays a protective role against quercetin-induced apoptosis. Moreover, functional studies revealed that quercetin activated autophagy by modulation of Akt-mTOR signaling and hypoxia-induced factor 1α (HIF-1α) signaling. Finally, a xenograft model provided additional evidence for occurrence of quercetin-induced apoptosis and autophagy in vivo. Together, our studies provided new insights regarding the biological and anti-proliferative activities of quercetin against gastric cancer, and may contribute to rational utility and pharmacological study of quercetin in future anti-cancer research.  相似文献   

6.
Colorectal cancer (CRC) and lung cancer (LC) occur at high incidence, and both can be effectively prevented by dietary vegetable consumption. This makes these two types of cancer highly suitable for elucidating the underlying molecular mechanisms of cancer chemoprevention. Numerous studies have shown that vegetables exert their beneficial effects through various different mechanisms, but effects on the genome level remain mostly unclear. This review evaluates current knowledge on the mechanisms of CRC and LC prevention by vegetables, thereby focusing on the modulation of gene and protein expressions. The majority of the effects found in the colon are changes in the expression of genes and proteins involved in apoptosis, cell cycle, cell proliferation and intracellular defense, in favor of reduced CRC risk. Furthermore, vegetables and vegetable components changed the expression of many more genes and proteins involved in other pathways for which biologic meaning is less clear. The number of studies investigating gene and protein expression changes in the lungs is limited to only a few in vitro and animal studies. Data from these studies show that mostly genes involved in biotransformation, apoptosis and cell cycle regulation are affected. In both colon and lungs, genomewide analyses of gene and protein expression changes by new genomics and proteomics technologies, as well as the investigation of whole vegetables, are few in number. Further studies applying these 'omics' approaches are needed to provide more insights on affected genetic/biologic pathways and, thus, in molecular mechanisms by which different chemopreventive compounds can protect against carcinogenesis. Particularly studies with combinations of phytochemicals and whole vegetables are needed to establish gene expression changes in the colon, but especially in the lungs.  相似文献   

7.
Epidemiological studies over the last few decades have shown a strong influence of obesity on colon cancer risk and its progression. These studies have primarily focussed on the role of adipokines in driving cancer progression. We investigated the incidence of cancerous polyp formation and tumor progression in presence and absence of functional leptin along with exploring the role of tumor necrosis factor α (TNFα), under obese condition. By utilizing diet induced obese and genetically obese mice, carcinogen induced colon polyp formation was investigated. Experiments were performed using tumor tissues and cell lines to delineate the inter-relationship between leptin and TNFα. Data shown in this report indicates that in leptin knockdown obese mice, AOM/DSS induced polyps are smaller and lesser in numbers as compared to AOM/DSS induced polyps in diet induced obese mice. Further in vitro experiments suggest that abrogation of leptin associated pathways promote TNFα induced apoptosis. Mechanistically, we report that TNFα induces p53 independent cell death through up regulation of p53 upregulated modulator of apoptosis (PUMA). TNFα induced PUMA was inhibited upon pre- exposure of cells to leptin, prior to TNFα treatment. Collectively these results indicate that obesity due to leptin non-functionality facilitates TNFα induced colon cancer cell death.  相似文献   

8.
《Autophagy》2013,9(9):966-978
Quercetin, a dietary antioxidant present in fruits and vegetables, is a promising cancer chemopreventive agent that inhibits tumor promotion by inducing cell cycle arrest and promoting apoptotic cell death. In this study, we examined the biological activities of quercetin against gastric cancer. Our studies demonstrated that exposure of gastric cancer cells AGS and MKN28 to quercetin resulted in pronounced pro-apoptotic effect through activating the mitochondria pathway. Meanwhile, treatment with quercetin induced appearance of autophagic vacuoles, formation of acidic vesicular organelles (AVOs), conversion of LC3-I to LC3-II, recruitment of LC3-II to the autophagosomes as well as activation of autophagy genes, suggesting that quercetin initiates the autophagic progression in gastric cancer cells. Furthermore, either administration of autophagic inhibitor chloroquine or selective ablation of atg5 or beclin 1 using small interfering RNA (siRNA) could augment quercetin-induced apoptotic cell death, suggesting that autophagy plays a protective role against quercetin-induced apoptosis. Moreover, functional studies revealed that quercetin activated autophagy by modulation of Akt-mTOR signaling and hypoxia-induced factor 1α (HIF-1α) signaling. Finally, a xenograft model provided additional evidence for occurrence of quercetin-induced apoptosis and autophagy in vivo. Together, our studies provided new insights regarding the biological and anti-proliferative activities of quercetin against gastric cancer, and may contribute to rational utility and pharmacological study of quercetin in future anti-cancer research.  相似文献   

9.
陈敏  李逐波 《生命科学》2011,(5):487-491
大蒜是一种古老的药用植物,具有广谱的抗肿瘤作用,发挥其主要抗肿瘤作用的是多种烯丙基有机硫化物。从大蒜中有机硫化物调节致癌物的代谢、抑制肿瘤细胞周期、诱导肿瘤细胞凋亡、消除自由基和抗氧化等方面,对其抗肿瘤作用机制研究进展作一综述。  相似文献   

10.
An important and promising group of compounds that have a chemopreventive property are organosulfur compounds, such as isothiocyanates (ITCs). In recent years, it has been shown that ITCs induce apoptosis in various cancer cell lines and experimental rodents. During the course of apoptosis induction by ITC, multiple signal-transduction pathways and apoptosis intermediates are modulated. We have also clarified the molecular mechanism underlying the relationship between cell cycle arrest and apoptosis induced by benzyl isothiocyanate (BITC), a major ITC compound isolated from papaya. The exposure of cells to BITC resulted in the inhibition of the G2/M progression that coincided with not only the up-regulated expression of the G2/M cell cycle arrest-regulating genes but also the apoptosis induction. The experiment using the phase-specific synchronized cells demonstrated that the G2/M phase-arrested cells are more sensitive to undergoing apoptotic stimulation by BITC than the cells in other phases. We identified the phosphorylated Bcl-2 as a key molecule linking the p38 MAPK-dependent cell cycle arrest with the JNK activation by BITC. We also found that BITC induced the cytotoxic effect more preferentially in the proliferating normal human colon epithelial cells than in the quiescent cells. Conversely, treatment with an excessive concentration of BITC resulted in necrotic cell death without DNA ladder formation. This review addresses the biological impact of cell death induction by BITC as well as other ITCs and the involved signal transduction pathways.  相似文献   

11.
Cancer results from an imbalance between cell cycle progression and apoptosis. Therefore, most anticancer drugs exert their antiproliferative and cytotoxic activity via cell cycle arrest and induction of apoptosis, a controlled form of cell death that is dysregulated in cancer. Many polyadenylation trans-acting factors, including polyadenylate polymerase (PAP), are increasingly found to be involved in cell cycle, apoptosis and cancer prognosis. The objective of the present study was to identify PAP modulations in the response of two epithelial cancer cell lines (HeLa and MCF-7) to apoptosis induction by the anticancer drugs etoposide and cordycepin. Cells were assessed for PAP activity and isoforms by the highly sensitive PAP activity assay and Western blotting, respectively. Induction of apoptosis was determined by endonucleosomal DNA cleavage, 4'6-diamidino-2-phenylindol (DAPI) staining and caspase-6 activity assay, whereas cytotoxicity and cell cycle status were assessed by trypan blue staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Our results indicate that PAP changes very early in response to either etoposide or cordycepin treatment, even prior to the hallmarks of apoptosis (chromatin condensation and cleavage), in both cell lines tested, but in a different mode. Our results suggest, for the first time, that in the epithelial cancer cell lines used, PAP modulations follow cell cycle progression rather than the course of apoptosis.  相似文献   

12.
Liao CF  Luo SF  Shen TY  Lin CH  Chien JT  Du SY  Jiang MC 《BMB reports》2008,41(3):210-216
CSE1L/CAS, a microtubule-associated, cellular apoptosis susceptibility protein, is highly expressed in various cancers. Microtubules are the target of paclitaxel-induced apoptosis. We studied the effects of increased or reduced CAS expression on cancer cell apoptosis induced by chemotherapeutic drugs including paclitaxel. Our results showed that CAS overexpression enhanced apoptosis induced by doxorubicin, 5-fluorouracil, cisplatin, and tamoxifen, but inhibited paclitaxel-induced apoptosis of cancer cells. Reductions in CAS produced opposite results. CAS overexpression enhanced p53 accumulation induced by doxorubicin, 5-fluorouracil, cisplatin, tamoxifen, and etoposide. CAS was associated with alpha-tubulin and beta-tubulin and enhanced the association between alpha-tubulin and beta-tubulin. Paclitaxel can induce G2/M phase cell cycle arrest and microtubule aster formation during apoptosis induction, but CAS overexpression reduced paclitaxel-induced G2/M phase cell cycle arrest and microtubule aster formation. Our results indicate that CAS may play an important role in regulating the cytotoxicities of chemotherapeutic drugs used in cancer chemotherapy against cancer cells.  相似文献   

13.
14.
15.
WEHI-231 cells have been used extensively as a model of tolerance induction in B cells. Recent evidence has shown that anti-IgM treatment of WEHI-231 cells resulted in the induction of apoptosis. In this study, using acridine orange staining and flow cytometric analysis, we demonstrated that apoptotic cells are detected as a distinct population of cells separate from the cells in normal cell cycle progression. The validity of analysis gates was confirmed by cell sorting of the apoptotic population versus normal cells and subsequent gel analysis. Using this technique, we have demonstrated that F(ab')2 anti-mu, A23187, or PMA induced apoptosis in the WEHI-231 cells. The addition of LPS reversed apoptotic induction as seen previously with the WEHI-231 cell line. In contrast, however, PMA did not prevent the induction of apoptosis in anti-mu-treated cells. Additionally, we were interested in determining if the induction of apoptosis was restricted to a specific phase of cell cycle. Since growth inhibition results in most cells arresting in the G1 phase of cell cycle, we wanted to demonstrate apoptosis as a G1-dependent event. This was examined with WEHI-231 cells treated with known cell cycle inhibitors. Interestingly, inhibition of cells in each phase of cycle resulted in the induction of apoptosis. LPS was able to inhibit the induction of apoptosis with each of the cell cycle inhibitors except actinomycin D. Furthermore, we have demonstrated that the WEHI-231 cells contain a Ca(2+)-Mg(2+)-dependent preexisting endonuclease.  相似文献   

16.
The Epidermal Growth Factor (EGF) Receptor (EGFR) plays an important role in the growth and progression of breast cancer. Overexpression of EGFR or the high activity of EGFR signal pathway has been related with increases in cell proliferation and a poor prognosis in patients with breast cancer. Several human breast cancer cell lines depend on estrogen for their proliferation. EGF may bypass the requirement of estrogen for the proliferation of breast cancer cells. To evaluate this hypothesis, MCF-7 breast cancer cells were stimulated with EGF and the effects on cell proliferation, signal pathways, and cell cycle progression were determined. The results demonstrate that EGF stimulation in the absence of others growth factors induced a modest effect on cell proliferation and the induction of a cellular arrest in the G1 phase of the cell cycle. Although phosphorylation of AKT and ERK proteins were detected, this phosphorylation was insufficient to support of cell cycle progression. Cellular arrest in G1 phase was accompanied by an increase in p21CIP1 protein, down regulation of the BCL-2 protein, induction of caspase-8, and ARHI/NOEY2 an imprinted tumor suppressor gene. These results indicate that EGFR activation by itself is not sufficient for the proliferation of breast cancer cells and suggest the existence of a mechanism that induces apoptosis upon EGFR activation.  相似文献   

17.
Diallyl disulfide (DADS), an oil soluble constituent of garlic (Allium sativum), has been reported to cause antimutagentic and anticarcinogenic effects in vitro and in vivo by modulating phases I and II enzyme activities. In recent years, several studies suggested that the chemopreventive effects of DADS can also be attributed to induction of cell cycle arrest and apoptosis in cancer cells. In the present study, we reported that DADS-induced cell cycle arrest at G2/M and apoptosis in human A549 lung cancer cells in a time- and dose-dependent manner. Additionally, a significant increase of intracellular reactive oxygen species (ROS) was induced in A549 cells less than 0.5 h after DADS treatment, indicating that ROS may be an early event in DADS-modulated apoptosis. Treatment of A549 cells with N-acetyl cysteine (NAC) completely abrogated DADS-induced cell cycle arrest and apoptosis. The result indicated that oxidative stress modulates cell proliferation and cell death induced by DADS.  相似文献   

18.
Methylxantine derivative, caffeine, is known to prevent the p53-dependent apoptosis pathway via inhibition of ATM (ataxia telangiectasia mutated) kinase, which activates p53 by phosphorylation of the Ser-15 residue. In contrast, it has been reported that caffeine induces p53-mediated apoptosis through Bax protein in non-small-cell lung cancer cells. Therefore, the effects of caffeine on cellular growth in malignant cells are controversial. We investigated the effects of caffeine on cell proliferation, cell cycle progression, and induction of apoptosis in NB4 promyelocytic leukemia cells containing wild-type p53. Caffeine suppressed the cellular growth of NB4 cells in a dose- and time-dependent manner. Caffeine induced G(2)/M phase cell cycle arrest in NB4 cells in association with the induction of phosphorylation at the Ser-15 residue of p53 and induction of tyrosine phosphorylation of cdc2. Expression of Bax protein was increased in NB4 cells after treatment with caffeine. Interestingly, the antisense oligonucleotides for p53 significantly reduced p53 expression and caffeine-induced G(2)/M phase cell cycle arrest in NB4 cells. These results suggest that caffeine induces cell cycle arrest and apoptosis in association with activation of p53 by a novel pathway to phosphorylate the Ser-15 residue and induction of phosphorylation of cdc 2 in leukemic cells with normal p53.  相似文献   

19.
Dysfunction of the UPS (ubiquitin—proteasome system) has been implicated in dopaminergic neuronal death in PD (Parkinson's disease). Recent studies suggest that unregulated cell cycle events play a key role in neuronal death. In this study, the effects of UPS dysfunction on cell cycle events in neuronal differentiated PC12 cells were analysed using a specific inhibitor of proteasome, lactacystin. Lactacystin induced apoptosis, G2/M cell cycle arrest and sustained the phosphorylation of the pRB (retinoblastoma protein), the key molecular process of G1/S transition, in neuronal PC12 cells. Furthermore, inhibition of cell cycle progression protected against lactacystin‐induced cell apoptosis. Finally, we determined that lactacystin activated the ERK signalling pathway. Inhibition of ERK1/2 activation by MEK‐1 inhibitor PD98059 decreased cell cycle aberrant and prevented apoptosis induced by lactacystin. These results indicate that aberrant cell cycle events contribute to apoptotic death induced by UPS dysfunction.  相似文献   

20.
Antony ML  Kim SH  Singh SV 《PloS one》2012,7(2):e32267
Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, decreases viability of cancer cells by causing apoptosis but the mechanism of cell death is not fully understood. The present study was undertaken to determine the role of Bcl-2 family proteins in BITC-induced apoptosis using MDA-MB-231 (breast), MCF-7 (breast), and HCT-116 (colon) human cancer cells. The B-cell lymphoma 2 interacting mediator of cell death (Bim) protein was dispensable for proapoptotic response to BITC in MCF-7 and MDA-MB-231 cells as judged by RNA interference studies. Instead, the BITC-treated MCF-7 and MDA-MB-231 cells exhibited upregulation of p53 upregulated modulator of apoptosis (PUMA) protein. The BITC-mediated induction of PUMA was relatively more pronounced in MCF-7 cells due to the presence of wild-type p53 compared with MDA-MB-231 with mutant p53. The BITC-induced apoptosis was partially but significantly attenuated by RNA interference of PUMA in MCF-7 cells. The PUMA knockout variant of HCT-116 cells exhibited significant resistance towards BITC-induced apoptosis compared with wild-type HCT-116 cells. Attenuation of BITC-induced apoptosis in PUMA knockout HCT-116 cells was accompanied by enhanced G2/M phase cell cycle arrest due to induction of p21 and down regulation of cyclin-dependent kinase 1 protein. The BITC treatment caused a decrease in protein levels of Bcl-xL (MCF-7 and MDA-MB-231 cells) and Bcl-2 (MCF-7 cells). Ectopic expression of Bcl-xL in MCF-7 and MDA-MB-231 cells and that of Bcl-2 in MCF-7 cells conferred protection against proapoptotic response to BITC. Interestingly, the BITC-treated MDA-MB-231 cells exhibited induction of Bcl-2 protein expression, and RNA interference of Bcl-2 in this cell line resulted in augmentation of BITC-induced apoptosis. The BITC-mediated inhibition of MDA-MB-231 xenograft growth in vivo was associated with the induction of PUMA protein in the tumor. In conclusion, the results of the present study indicate that Bim-independent apoptosis by BITC in cancer cells is mediated by PUMA.  相似文献   

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