Indole-3-Carbinol Potent Oral Anticancer Activity

#C176 SR13668: A Highly Optimized AKT Inhibitor Based on Indole-3-Carbinol Possesses Potent Oral Anticancer Activity, and Induces G1 Cell Cycle Arrest and Apoptosis in vitro and in vivo.

Ling Jong, Wan-Ru Chao, Khalid Amin, Glenn Rice,

SRI International, Menlo Park, CA.

Indole-3-carbinol (I3C), found exclusively in cruciferous vegetables, has established effectiveness against various cancers and is currently in several clinical trials. I3C is a prodrug and it must be acted upon by gastric acid to form active acid condensation products (oligomers) that are responsible for its in vivo anticancer activity.

Unfortunately, variations in stomach pH change the nature of the oligomers formed, causing insurmountable complexity and uncertainty that hamper I3C’s suitability as a potential cancer preventive.

Here, we reported the discovery of SR13668, developed from the four active I3C oligomers, as a result of lead-based rational drug design using computational modeling to optimize I3C’s anticancer activities, improve its potency, maintain or improve its safety profile and minimize its undesirable metabolic and estrogenic characteristics.

SR13668 exhibits potent oral antitumor activity against both estrogen-dependent (MCF-7) and -independent breast (MDA-MB-231), and drug-resistant ovarian (SKOV-3) tumors, and is nonmutagenic in Ames tests.

In vitro and in vivo experiments demonstrate that SR13668 exhibits encouraging I3C-like activities—for instance, demonstrating antiestrogenic activity, inducing G1 cell cycle arrest and apoptosis, inhibiting phospho-AKT (pAKT), and preventing cancer cell invasion, but at concentrations 10-100 fold lower than I3C or DIM.

SR13668 exhibits 80% antiestrogenic activity at a concentration of 10 µM in human Ishikawa endometrial adenocarcinoma cells, and expressed no intrinsic estrogenic activity, whereas DIM, the major active I3C oligomer, showed significant estrogenic activity at 10 µM.

In vivo, oral administration of SR13668 completely inhibited pAKT levels in MDA-MB-468 tumors, as measured by immunohistochemistry staining.

The mice showed no evidence of toxicity through the course of treatment (30 days); glucose utilization is unaltered and early toxicology is encouraging.

It is hypothesized that part of I3C’s anticancer activity may also stem from its ability to induce specific cytochrome P450 phase I (CYP1A) and phase II drug-metabolizing enzymes involved in estrogen and carcinogen metabolism, but CYP1A1 expression also has a strong positive correlation with the aryl hydrocarbon receptor (AhR), which is reported to mediate TCDD’s toxic effects.

Our in vivo studies show that SR13668 at 30 mg/kg only causes 1.6-fold induction of CYP1A1-associated 7-ethoxyresorufin O-deethylase (EROD), while ICZ, one of the I3C oligomers, causes 17-fold EROD induction at a low dose level of 1.3 mg/kg.

Collectively, we demonstrate our novel dietary indole analog SR13668 acts by I3C and DIM-like mechanisms but has substantially improved potency and stability over I3C and DIM in inhibiting important molecular targets of apoptosis, drug resistance and tumorigenesis.

(Supported by grants from California Breast Cancer Research Program (CBCRP) and NCI Rapid Access to Preventive Intervention Development (RAPID) program)

Frontiers in Cancer Prevention Research, 2003 AACR

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