Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological studies have suggested that the consumption of fruits and vegetables that provide several classes of compounds, including Indole-3-carbinol (I3C), may have chemopreventive activity against breast cancer. Several in vitro and in vivo animal studies also provide convincing evidence for the anti-tumor activity of I3C, however, the molecular mechanism(s) by which I3C exerts its biological effects on breast cancer cells has not been fully elucidated. In this study, we investigated the effects of I3C in Her-2/neu over-expressing MDA-MB-435 breast cancer cells and compared these results with parental cells transfected with control vector. We focused our investigation in elucidating the molecular mechanism(s) by which I3C induces apoptosis in breast cancer cells. Our data show that I3C inhibits breast cancer cell growth in a dose dependent manner in Her-2/neu over-expressing and in normal Her-2/neu expressing cells. Induction of apoptosis was also observed in these cell lines when treated with I3C, as measured by poly (ADPribose) polymerase (PARP) and caspase-3 activation. In addition, we found that I3C up-regulates Bax, down-regulates Bcl-2 and, thereby, increased the ratio of Bax to Bcl-2 favoring apoptosis. These results suggest that the alteration in the expression of these genes may play an important role in mediating the biological effects of I3C. Moreover, we also show the cellular localization of Bax by confocal microscopy, which showed diffuse distribution of Bax throughout the cytoplasmic compartment in breast cancer cells in control culture. However, in I3C treated cells, Bax showed a punctate pattern of distribution that was localized in the mitochondria. From these results, we conclude that the over-expression and translocation of Bax to mitochondria causes mitochondrial depolarization and activation of caspases, which may be one of the mechanism(s) by which I3C induces apoptotic processes in I3C treated breast cancer cells. Overall, our present data provide a novel molecular mechanism(s) by which I3C elicits its biological effects on both Her-2/neu over-expressing and with normal Her-2/neu expressing breast cancer cells, suggesting that I3C could be an effective agent in inducing apoptosis in breast cancer cells.
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PMID:Translocation of Bax to mitochondria induces apoptotic cell death in indole-3-carbinol (I3C) treated breast cancer cells. 1112 63

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1) CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer.
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PMID:Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. 1142 Jul 5

Dietary indole-3-carbinol (I3C) has clinical benefits for both cervical cancer and laryngeal papillomatosis, and causes apoptosis of breast cancer cells in vitro. We asked whether I3C and its major acid-catalyzed condensation product diindolylmethane (DIM), which is produced in the stomach after consumption of cruciferous vegetables, could induce apoptosis of cervical cancer cell lines. We also asked whether this effect could be observed in vivo. In vitro, both I3C and DIM caused accumulation of DNA strand breaks in three cervical cancer cell lines. Induction of apoptosis was confirmed by nuclear morphology, nucleosome leakage, altered cytoplasmic membrane permeability and caspase 3 activation. Neither I3C nor DIM caused apoptotic changes in normal human keratinocytes. In C33A cervical cancer cells, DIM was more potent than I3C [dose at which the number of viable cells was 50% of that in untreated cultures (LD(50)) = 50-60 micromol/L for DIM and 200 micromol/L for I3C in a mitochondrial function assay] and faster acting. Furthermore, I3C reduced Bcl-2 protein in a time- and dose-dependent manner. In HPV16-transgenic mice, which develop cervical cancer after chronic estradiol exposure, apoptotic cells were detected in cervical epithelium by TdT-mediated dUTP nick-end labeling staining and by immunohistochemical staining of active caspase 3 only in mice exposed to 17beta-estradiol (E2) and fed I3C. Rare apoptotic cells were also observed by hematoxylin and eosin staining in the spinous layer of the cervical epithelium in both control and transgenic mice. Estradiol reduced the percentage of these late-stage apoptotic cells in the cervical epithelium of transgenic, E2-treated mice, but this reduction was prevented by I3C. These data confirm the proapoptotic action of I3C on transformed cells in vitro, extend the observations to cervical cancer cells and to DIM and show for the first time that dietary I3C results in increased apoptosis in target tissues in vivo.
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PMID:Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. 1173 83

3,3'-Diindolylmethane (DIM) is a major in vivo derivative of the putative anticancer agent indole-3-carbinol (I3C), which is present in vegetables of the Brassica genus. At concentrations above 10 microM, DIM inhibited DNA synthesis and cell proliferation in both estrogen receptor replete (MCF-7) and deficient (MDA-MB-231) human breast cancer cells in a concentration- and time-dependent manner. These antiproliferative effects were accompanied by characteristic indications of programmed cell death in both cell lines, including externalization of phosphatidylserine, chromatin condensation, and DNA fragmentation. Furthermore, Western and Northern blot analyses, as well as coimmunoprecipitation assays, revealed that in both MCF-7 and MDA-MB-231 cells, DIM treatment decreased total transcript and protein levels of the apoptosis inhibitory protein Bcl-2, and the amount of Bcl-2 bound to the pro-apoptotic protein Bax. DIM treatment also caused an increase in Bax protein levels, but did not affect the level of Bax that was bound to Bcl-2. As a functional test of the role of Bcl-2 down-regulation in the DIM-induced apoptotic response, ectopic expression of Bcl-2 in MCF-7 cells was shown to attenuate the apoptotic effect of DIM. These results demonstrate that DIM can induce apoptosis in breast cancer cells independent of estrogen receptor status by a process that is mediated by the modulated expression of the Bax/Bcl-2 family of apoptotic regulatory factors.
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PMID:Bcl-2 family-mediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells. 1193 41

Recent results from epidemiology, in vitro cell culture and in vivo (animal and human) studies have suggested the benefits of indole-3-carbinol (I3C) for the prevention of many types of cancer, including breast cancer. However, there are no reports, to the best of our knowledge, on the effect of I3C on isogenic nontumorigenic and tumorigenic breast epithelial cells, and there is a significant void in our understanding of the molecular mechanism(s) by which I3C induces apoptotic cell death in breast cancer cells. To fill this gap in our understanding, we conducted experiments to investigate the effects of I3C on an isogenic nontumorigenic (MCF10A) and tumorigenic (MCF10CA1a [CA1a]) breast epithelial cells. Here we show that CA1a cells are more sensitive to low concentration of I3C in terms of cell growth inhibition compared to MCF10A cells. We further report that I3C upregulates Bax/Bcl-2 ratio and downregulates Bcl-xL expression in CA1a cells but not in MCF10A cells. We also report, for the first time, that I3C induces Bax translocation to the mitochondria, causing mitochondrial depolarization, resulting in the loss of mitochondrial potential leading to the release of cytochrome c and subsequent cell death in CA1a cells but not in MCF10A cells. From these results, we conclude that I3C selectively induces apoptosis in breast cancer cells, but not in nontumorigenic breast epithelial cells, suggesting the potential therapeutic benefit of I3C against breast cancer.
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PMID:Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. 1279 10

Indole-3-carbinol (I3C), a natural component of Brassica vegetables, has been found to be a promising cancer preventive agent. However, the precise molecular mechanism(s) by which I3C exerts its inhibitory effects on cancer cells has not been fully elucidated. We investigated the molecular mechanism of action of I3C during apoptotic processes in breast epithelial cells. Nontumorigenic and tumorigenic breast epithelial cells were exposed to I3C, and growth inhibition, apoptosis and expression of genes involved in apoptotic processes were measured. Translocation of Bax to the mitochondria was accessed by confocal imaging. Mitochondrial potential and cytochrome c release also were measured. We found that I3C inhibited the growth of breast cancer cells and induced apoptosis in these cells, concomitant with upregulation of Bax, and downregulation of Bcl-2. I3C induced translocation of Bax to the mitochondria in both tumorigenic and nontumorigenic cells, but concomitant loss of mitochondrial potential, release of cytochrome c and induction of apoptosis were observed only in cancer cells. In conclusion, I3C exerts its effects by regulating cell cycle and by altering the expression of genes involved in apoptotic pathway. The translocation of Bax to the mitochondria alone is not sufficient during I3C-induced apoptosis. Translocation of Bax followed by mitochondrial depolarization and cytochrome c release is necessary, which may be responsible for selective induction of apoptosis in cancer cells, supporting the potential preventive and/or therapeutic benefit of I3C against cancers.
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PMID:Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. 1284 Feb 20

Induction of apoptosis is an approach to suppress carcinogenesis. The effects of a 12-week treatment of female Sprague-Dawley rats with indole-3-carbinol (I3C), beta-naphthoflavone or vehicle (40% ethanol in corn oil), by oral gavages starting 3 weeks after initiation of mammary tumorigenesis with 7,12-dimethylbenz[alpha]anthracene, on apoptotic activities in the mammary adenocarcinomas were examined. Apoptotic cells in tumor sections were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and quantitated by light microscopy and an Image-Plus Program. Activities of caspase-3, caspase-8 and caspase-9 were determined by colorimetric assays using the specific substrate and total tumor protein. There were no significant treatment-related effects on the numbers of apoptotic cells and caspase activities in the mammary adenocarcinomas. Likewise, protein expression levels of Bcl-2 and Bax genes in these tumors, determined by Western blot analysis, showed no treatment-related stimulation of apoptotic process. In the absence of tumorigenesis, the activities of caspase-3, caspase-8 and caspase-9 were increased up to approximately 3.6-fold in the mammary gland of rats treated with I3C at 5 or 25 mg/kg of body weight for 4 or 10 days. The I3C-effected induction of caspase-3 activity in the mammary gland was further confirmed by the cleavage of poly (ADP-ribose) polymerase. Treatment of rats with 3,3'-diindolylmethane, a major product of I3C in vivo, at the dose levels equimolar to those of I3C above, did not increase the caspase activities in the mammary gland. Thus, this I3C dimer does not seem to account for the increases of apoptotic activities in the mammary gland observed with I3C. The results suggest that increase of apoptosis in the mammary gland induced by I3C before initiation of tumorigenesis may contribute to suppression of tumor development.
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PMID:Effects of treatment of rats with indole-3-carbinol on apoptosis in the mammary gland and mammary adenocarcinomas. 1289 30

Mounting preclinical and clinical evidence indicate that indole-3-carbinol (I3C), a key bioactive food component in cruciferous vegetables, has multiple anticarcinogenic and antitumorigenic properties. Evidence that p21, p27, cyclin-dependent kinases, retinoblastoma, Bax/Bcl-2, cytochrome P-450 1A1 and GADD153 are targets for I3C already exists. Modification of nuclear transcription factors including Sp1, estrogen receptor, nuclear factor kappaB and aryl hydrocarbon receptor may represent a common site of action to help explain downstream cellular responses to dietary I3C and, ultimately, to its anticancer properties. While the current information is intriguing, future I3C research needs to focus on why these changes in nuclear transcription factors occur and how they relate to phenotypic responses and the quantity and duration of exposure to I3C and its dimer 3,3'-diindolylmethane.
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PMID:Targets for indole-3-carbinol in cancer prevention. 1568 Nov 63

Indole-3-carbinol, found in Brassica species vegetables (such as cabbage, cauliflower, and brussels spouts), exhibits antitumor effects through poorly defined mechanisms. Because several genes that regulate apoptosis, proliferation, and metastasis are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that indole-3-carbinol must mediate its activity through NF-kappaB modulation. We demonstrated that indole-3-carbinol suppressed constitutive NF-kappaB activation and activation induced by tumor necrosis factor (TNF), interleukin-1beta (IL-1beta), phorbol 12-myristate 13-acetate (PMA), lipopolysaccharide (LPS), and cigarette smoke; the suppression was not cell type specific, because activation was inhibited in myeloid, leukemia, and epithelial cells. This activation correlated with the sequential suppression of the IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, p65 acetylation, and NF-kappaB-dependent reporter gene expression. The NF-kappaB-regulated gene products cyclin D1, cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), survivin, inhibitor-of-apoptosis protein-1 (IAP1), IAP2, X chromosome-linked IAP (XIAP), Bcl-2, Bfl-1/A1, TNF receptor-associated factor-1 (TRAF1), and Fas-associated death domain protein-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) were all down-regulated by indole-3-carbinol. This down-regulation led to the potentiation of apoptosis induced by cytokines and chemotherapeutic agents. Indole-3-carbinol suppressed constitutive NF-kappaB activation in mononuclear cells derived from bone marrow of acute myelogenous leukemia patients, and this correlated with inhibition of cell growth. Overall, our results indicated that indole-3-carbinol inhibits NF-kappaB and NF-kappaB-regulated gene expression and that this mechanism may provide the molecular basis for its ability to suppress tumorigenesis.
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PMID:Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. 1581 58

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11


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