Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cells requires the induced production of activated p53 tumor suppressor protein

Hsu, Jocelyn C.; Dev, Anurupa; Wing, Aimee; Brew, Christine Taylor; Bjeldanes, Leonard F.; Firestone, Gary L.

doi:10.1016/j.bcp.2006.08.012

Cited by 42 publications

(27 citation statements)

References 41 publications

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“…Conversely, dietary indoles derived from cruciferous vegetables, such as indole-3-carbinol (I3C), and 3,3′diindolyl-methane (DIM), exhibit significant anticancer efficacy in vivo (4) and in vitro (5,6). The dietary indoles (I3C, DIM) exert anticancer activity by inducing apoptosis (4-6), exert antimetastatic properties (4,10), inhibit angiogenesis gene products (11), and induce cell cycle arrest (7)(8)(9) in G 1 (5,9) through modulation of cyclin-cdk holoenzyme components. These indoles down-regulate cyclin D1 (4,7,12) and its associated cdk4 (7,12) and cdk6 (5,7,9,12) holoenzyme components in mid-G 1 .…”

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confidence: 99%

3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

Khwaja

Wynne

Posey

et al. 2009

Cancer Prevention Research

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The p75 NTR functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with the nonsteroidal anti-inflammatory drug, indomethacin, induced p75 NTR expression in the T24 cancer cell line leading to p75 NTR -mediated decreased survival. Utilizing the indole moiety of indomethacin as a pharmacophore, we identified in rank-order with least efficacy, ketorolac, etodolac, indomethacin, 5-methylindole-3-acetic acid, indole-3-carbinol, and 3,3′-diindolylmethane (DIM) exhibiting greatest activity for induction of p75 NTR levels and inhibition of cell survival. Prostate (PC-3, DU-145) and bladder (T24) cancer cells were more sensitive to DIM induction of p75 NTR -associated loss of survival than breast (MCF7) and fibroblast (3T3) cells. Transfection of the PC-3 prostate cell line with a dominant-negative form of p75 NTR before DIM treatment significantly rescued cell survival demonstrating a cause and effect relationship between DIM induction of p75 NTR levels and inhibition of survival. Furthermore, siRNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75 NTR by DIM in the PC-3 prostate cell line. DIM treatment induced phosphorylation of p38 MAPK as early as within 1 minute. Collectively, we identify DIM as an indole capable of inducing p75 NTR -dependent apoptosis via the p38 MAPK pathway in prostate cancer cells.

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confidence: 99%

3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

Khwaja

Wynne

Posey

et al. 2009

Cancer Prevention Research

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“…I3C can suppress invasion and migration of human breast cancer cells (16) and stimulate IFN-␥ receptor production and IFN-␥ responsiveness (17). In other types of human reproductive cancer cells, I3C has been shown to have strong antiproliferative effects (5,6,(18)(19)(20)(21), and it alters immune function in vivo (22). Despite compelling evidence for the potent anticancer properties of this indole, the direct cellular target(s) of I3C that play a central role in the striking cell-cycle effects of this phytochemical have not been uncovered.…”

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confidence: 99%

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

Nguyen¹,

Aronchik²,

Brar³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as broccoli, cabbage, and Brussels sprouts, induces a G 1 cell-cycle arrest of human breast cancer cells, although the direct cellular targets that mediate this process are unknown. Treatment of highly invasive MDA-MB-231 breast cancer cells with I3C shifted the stable accumulation of cyclin E protein from the hyperactive lower-molecular-mass 35-kDa form that is associated with cancer cell proliferation and poor clinical outcomes to the 50-kDa cyclin E form that typically is expressed in normal mammary tissue. An in vitro cyclin E processing assay, in combination with zymography, demonstrated that I3C, but not its natural dimer, 3,3 -diindolylmethane, disrupts proteolytic processing of the 50-kDa cyclin E into the lower-molecular-mass forms by direct inhibition of human neutrophil elastase enzymatic activity. Analysis of elastase enzyme kinetics using either cyclin E or N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanalide as substrates demonstrated that I3C acts as a noncompetitive inhibitor of elastase activity with an inhibitory constant of Ϸ12 M. Finally, siRNA ablation of neutrophil elastase protein production in MDA-MB-231 cells mimicked the I3C-disrupted processing of the 50-kDa cyclin E protein and the indole-induced cell-cycle arrest. Taken together, our results demonstrate that elastase is the first identified specific target protein for I3C and that the direct I3C inhibition of elastase enzymatic activity implicates the potential use of this indole, or related compounds, in targeted therapies of human breast cancers where high elastase levels are correlated with poor prognosis.A critical challenge in controlling breast cancer is the identification of therapeutic agents that can effectively control the growth of both estrogen-responsive and nonresponsive breast cancer cells with reduced side effects, especially during prolonged treatments. Epidemiological studies show that frequent consumption of certain vegetables is associated with a lower incidence of cancers at various sites (1). For example, the consumption of Brassica (cruciferous) vegetables, such as cabbage, broccoli, and Brussels sprouts, is directly associated with decreased risk of reproductive tissue cancers in humans (2, 3) and reduced tumor incidence in experimental animals (4). These studies implicate the existence of specific biologically active phytochemicals that represent a largely untapped source of potent chemotherapeutic agents. One such promising molecule is indole-3-carbinol (I3C), a natural compound derived from glycobrassicin in Brassica vegetables, which has been shown to exhibit potent anticarcinogenic properties in a wide range of cancers such as lung, liver, colon, cervical, endometrial, prostate, and breast cancer (5-7). In addition, out of broad spectrum of analyzed phytochemicals, I3C was 1 of the few that tested positive as a chemopreventative agent in a panel of short-term bioassays relevant to carcinogen-induced DNA damage, tumor initiat...

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“…However, there is as yet no clearly established therapy for reversing liver fibrosis. As one of the bioactive components in cruciferous vegetables, I3C's anticarcinogenic effect and several of its mechanisms have been raised into the spotlight (Hsu et al, 2006;Shen et al, 2008;Acharya et al, 2010;Guo et al, 2010;Tsai et al, 2010). But little is known about the effect of I3C on liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…A broad spectrum of biological effects of I3C has been reported, such as antiinflammation, antineoplasm, antimutagenesis, and antioxidation (Donald et al, 2004;Tsai et al, 2010). As a nutritional supplement, I3C has received attention over the years as a promising preventive and treatment agent for breast cancer and other types of cancers (Hsu et al, 2006;Acharya et al, 2010). In a previous study, we used micro-Raman spectroscopy to show the protective effect of I3C on acute alcoholic liver injury in vivo (Shen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

RETRACTION: Indole-3-Carbinol Enhances the Resolution of Rat Liver Fibrosis and Stimulates Hepatic Stellate Cell Apoptosis by Blocking the Inhibitor of κB Kinase α/Inhibitor of κB-α/Nuclear Factor-κB Pathway

Ping

Gao²,

Qin³

et al. 2011

J Pharmacol Exp Ther

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Hepatic stellate cells (HSC) play a pivotal role in liver fibrosis, and the clearance of activated HSC by apoptosis is associated with the resolution of liver fibrosis. The development of strategies that promote this process in a selective way is therefore important. We evaluated the effects of indole-3-carbinol (I3C), a nutritional component derived from vegetables from the Brassica family, on liver fibrosis and HSC apoptosis. The in vivo therapeutic effects of I3C were monitored in three rat models of liver fibrosis induced by porcine serum, bile duct ligation, or multiple hepatotoxic factors, and its proapoptotic effect and molecular mechanism were studied in vitro in HSC-T6, a rat HSC line. The results showed that I3C treatment significantly reduced the number of activated HSC in the livers of rats with liver fibrosis. In histopathology, I3C reduced hepatocyte degeneration and necrosis, accelerated collagen degradation, and promoted the reversal of liver fibrosis. I3C prescribed to HSC-T6 resulted in morphologic alterations typical of apoptosis and DNA cleavage to a nucleosomal ladder. Moreover, I3C significantly increased the HSC-T6 apoptosis rate and the expression ratio of Bax to Bcl-2. High-throughput protein array analysis indicated that the tumor necrosis factor-␣/nuclear factor-B (NF-B) signal pathway participated in I3C-induced HSC-T6 apoptosis. Western blot and electrophoretic mobilityshift assay confirmed that I3C inhibited the phosphorylation of inhibitor of B kinase ␣ and inhibitor of B-␣ and NF-B DNA binding activity. In conclusion, I3C could promote the reverse process of liver fibrosis in vivo and induce apoptosis of activated HSC in vitro, which indicates the use of I3C as a potential therapeutic agent in liver fibrosis treatment.

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Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cells requires the induced production of activated p53 tumor suppressor protein

Cited by 42 publications

References 41 publications

3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

RETRACTION: Indole-3-Carbinol Enhances the Resolution of Rat Liver Fibrosis and Stimulates Hepatic Stellate Cell Apoptosis by Blocking the Inhibitor of κB Kinase α/Inhibitor of κB-α/Nuclear Factor-κB Pathway

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