Dose-ranging study of Indole-3-Carbinol for breast cancer prevention

Wong, George Y.; Bradlow, Leon; Sepkovic, Daniel W.; Mehl, Stephanie; Mailman, Joshua Banks; Osborne, Michael P.

doi:10.1002/(sici)1097-4644(1997)28/29+<111::aid-jcb12>3.0.co;2-k

Cited by 107 publications

(55 citation statements)

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“…DNA ladder formation and PARP cleavage were also observed in I3C-treated prostate cancer cells. Collectively, these results clearly suggest that I3C inhibits the growth of prostate cancer cells and induces apoptosis, and that these results corroborate the ®ndings of many published studies in other cancer cell lines (Ge et al, 1996;Katdare et al, 1998;Wong et al, 1997;Cover et al, 1998).…”

Section: Discussionsupporting

confidence: 88%

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells

et al. 2001

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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 bene®t 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 hormonerelated 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 e ect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological e ects on prostate cancer cells. Here we report for the ®rst 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 e ects 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 e ects may also be mediated by the down-regulation of NF-kB 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 apoptosisrelated genes. These ®ndings suggest that I3C may be an e ective chemopreventive or therapeutic agent against prostate cancer. Oncogene (2001) 20, 2927 ± 2936.

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Section: Discussionsupporting

confidence: 88%

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells

et al. 2001

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“…It remains to be established whether a dose of this magnitude is clinically feasible considering the fact that the daily oral dosage used thus far in clinical trials of I3C has been 1/10 of this value. 16,17,39 As the hepatotoxicity of ET-743 in humans is not as severe as that in the rat, it is of course conceivable that the dose required for hepatoprotection in humans may be considerably lower than that necessary to protect the rat liver. Levels of I3C in the liver of rats that received dietary I3C have not been reported, except that in a study in which rats ingested radioactively labeled I3C (0.2% in the diet), hepatic steady-state levels of drug-derived species equivalent to 1.2 mol I3C per g tissue were measured.…”

Section: Discussionmentioning

confidence: 99%

“…16 There has also been a dose-finding study to prepare for its evaluation as a breast cancer preventive agent. 17 I3C is a potent inducer of cytochrome P450 enzymes, including CYP3A. 18 We surmised that it might possess pharmacologic properties that render it suitable as a candidate for hepatoprotection.…”

mentioning

confidence: 99%

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

Donald

Verschoyle

Greaves

et al. 2004

Intl Journal of Cancer

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ET-743, an experimental antitumor drug with promising activity in sarcoma, breast and ovarian carcinoma, is currently under phase 2 clinical evaluation. It is hepatotoxic in animals and patients. We tested the hypothesis that indole-3-carbinol (I3C), the hydrolysis product of glucosinolates occurring in cruciferous vegetables, may protect against ET-743-induced hepatotoxicity in the female Wistar rat, the animal species with the highest sensitivity toward the adverse hepatic effect of this drug. Hepatotoxicity was adjudged by measurement of plasma levels of bilirubin, alkaline phosphatase (ALP) and aspartate aminotransferase ( Key words: indole-3-carbinol; chemoprevention; ET-743; hepatotoxicityET-743 (ecteinascidin 743, trabectidin, Yondelis) is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinata. It possesses potent antineoplastic activity against a variety of human tumor xenografts grown in athymic mice, including melanoma and ovarian and breast carcinoma. [1][2][3] In clinical phase 1 studies of ET-743, promising responses were observed in patients with sarcoma, as well as breast and ovarian carcinoma, 4,5 and the drug is currently under intense investigation in a variety of phase 2 trials in cancer patients. However, myelotoxicity is dose-limiting. Furthermore, hepatotoxicity is frequently observed in the clinic, as reflected by reversible transaminitis and subclinical cholangitis, characterized by increases in alkaline phosphatase (ALP) and/or bilirubin. Treatment with ET-743 caused an increase in plasma levels of liver-specific enzymes and pathologic manifestations of cholangitis in most animal species in which it has been tested. 6,7 We recently showed that high-dose dexamethasone protects rats from ET-743-induced hepatotoxicity without compromising its antitumor activity. 8 Hepatoprotection was probably the consequence of a dramatic reduction by dexamethasone of hepatic levels of ET-743, which in turn was reasoned to be related to the ability of dexamethasone to increase the rate of metabolic detoxification of ET-743 via induction of the cytochrome P450 enzyme CYP3A in the liver. The potential use of high-dose dexamethasone as a hepatoprotectant in humans might be confounded by adverse effects, including diabetes mellitus, hypertension, arrhythmias, hypokalemia, psychosis, peptic ulceration and susceptibility to infection. 9,10 Indole-3-carbinol (I3C) is the aglycone of glucobrassicin, a microconstituent of cruciferous vegetables such as broccoli and Brussels sprouts. I3C, which is generated by glycoside-hydrolyzing enzymes when plant cells are disrupted by processing, cooking or mastication, possesses chemopreventive properties against chemically induced tumors in rodents at a variety of sites. [11][12][13][14] Clinical pilot studies of I3C have been conducted in patients with recurrent respiratory papillomatosis 15 and cervical intraepithelial neoplasia. 16 There has also been a dose-finding study to prepare for its evaluation as a breast cancer preventive agen...

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“…In controlled clinical trials, oral supplementation with 300-400 mg/d of I3C has consistently increased urinary 2OHE 1 levels or urinary 2OHE 1 :16αOHE 1 ratios in women [93][94][95][96][97]. Supplementation with 108 mg/day of DIM also increased urinary 2OHE 1 levels in postmenopausal women [98].…”

Section: Effects Of Indole-3-carbinol On Estrogen Metabolismmentioning

confidence: 99%

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

Higdon

Delage

Williams

et al. 2007

Pharmacological Research

917

697

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Cruciferous vegetables are a rich source of glucosinolates and their hydrolysis products, including indoles and isothiocyanates, and high intake of cruciferous vegetables has been associated with lower risk of lung and colorectal cancer in some epidemiological studies. Glucosinolate hydrolysis products alter the metabolism or activity of sex hormones in ways that could inhibit the development of hormone-sensitive cancers, but evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent. Organizations such as the National Cancer Institute recommend the consumption of 5-9 servings of fruits and vegetables daily, but separate recommendations for cruciferous vegetables have not been established. Isothiocyanates and indoles derived from the hydrolysis of glucosinolates, such as sulforaphane and indole-3-carbinol (I3C), have been implicated in a variety of anticarcinogenic mechanisms, but deleterious effects also have been reported in some experimental protocols, including tumor promotion over prolonged periods of exposure. Epidemiological studies indicate that human exposure to isothiocyanates and indoles through cruciferous vegetable consumption may decrease cancer risk, but the protective effects may be influenced by individual genetic variation (polymorphisms) in the metabolism and elimination of isothiocyanates from the body. Cooking procedures also affect the bioavailability and intake of glucosinolates and their derivatives. Supplementation with I3C or the related dimer 3,3′-diindolylmethane (DIM) alters urinary estrogen metabolite profiles in women, but the effects of I3C and DIM on breast cancer risk are not known. Small preliminary trials in humans suggest that I3C supplementation may be beneficial in treating conditions related to human papilloma virus infection, such as cervical intraepithelial neoplasia and recurrent respiratory papillomatosis, but larger randomized controlled trials are needed.

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Dose-ranging study of Indole-3-Carbinol for breast cancer prevention

Cited by 107 publications

References 8 publications

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis

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