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

Abstract

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...

Molecular Targets and Anticancer Potential of Indole-3-Carbinol and Its Derivatives

“…[106][107][108][109][110] Shertzer's group found that I3C protects mice from N-nitrosodimethylamine-mediated liver damage. 107 Treatment with 50 mg/kg body weight of I3C by gavage, 1 hr prior to NDMA, substantially protected against hemorrhagic lesions.…”

“…108 Tanaka's laboratory showed the inhibitory effect of I3C on diethylnitrosamine-induced hepatocarcinogenesis in male ACI/N rats and Donald's group found that I3C protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. 106 Goeger's group found that I3C inhibits aflatoxin B1 (AFB1) carcinogenesis through the modulation of the distribution and metabolism of AFB1 109 and Shukla's laboratory showed protective effects of I3C on cyclophosphamide-(CP) induced clastogenecity in mouse bone marrow cells. 110 The results revealed a significant inhibition in the frequencies of CP-induced CAs and aberrant cells in bone marrow cells of I3C-supplemented Swiss albino mice.…”

Indole-3-carbinol enhances anti-proliferative, but not anti-invasive effects of oxaliplatin in colorectal cancer cell lines

“…In recent years, a few studies have hinted at the potential for I3C to enhance chemotherapeutic regimes [12,29,30]. Yet to date, combinatorial options remain largely unexplored.…”

“…I3C is currently in clinical trial for treatment of recurrent respiratory papillomatosis [5,6] and cervical intraepithelial neoplasia [7,8] and has been shown to be well tolerated at doses up to 400mg/day [9]. Pharmacokinetic studies of I3C disposition have revealed systemic doses of up to 170μmol/L in tissue [10], which equates with in vitro efficacy particularly in the liver [11,12] which along with lymph nodes [13,14], is the major site for colorectal metastasis. I3C has been shown to exhibit both anti-proliferative and anti-invasive potential [15] via a variety of mechanisms, including up-regulation of E-cadherin and β-catenin at the cytoplasmic membrane [16,17], concurrent with down-regulation of nuclear β-catenin levels.…”

Trabectedin – the DNA minor groove binder

“…Индол-3-карбинол защищал крыс от токсического действия трабектедина при сохранении его терапевтического действия при РМЖ. Существенно, что защитный эффект индол-3-карбинола не сопровождался сни-жением содержания трабектедина в печени, что ука-зывает на наличие альтернативных путей его деток-сикации [53].…”