1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells.

Abstract

Indole-3-carbinol (I3C), a natural autolysis product of a gluccosinolate present in Brassica vegetables such as broccoli and cabbage, has anti-proliferative and anti-estrogenic activities in human breast cancer cells. A new and significantly more potent I3C analogue, 1-benzyl-I3C was synthesized, and in comparison to I3C, this novel derivative displayed an approximate 1000-fold enhanced potency in suppressing the growth of both estrogen responsive (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells (I3C IC(50) of 52 microM, and 1-benzyl-I3C IC(50) of 0.05 microM). At significantly lower concentrations, 1-benzyl-I3C induced a robust G1 cell cycle arrest and elicited the key I3C-specific effects on expression and activity of G1-acting cell cycle genes including the disruption of endogenous interactions of the Sp1 transcription factor with the CDK6 promoter. Furthermore, in estrogen responsive MCF-7 cells, with enhanced potency 1-benzyl-I3C down-regulated production of estrogen receptor-alpha protein, acts with tamoxifen to arrest breast cancer cell growth more effectively than either compound alone, and inhibited the in vivo growth of human breast cancer cell-derived tumor xenografts in athymic mice. Our results implicate 1-benzyl-I3C as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of indole-sensitive cancers.

• Authors: Hanh H Nguyen, Sergey N Lavrenov, Shyam N Sundar, David H H Nguyen, Min Tseng, Crystal N Marconett, Jenny Kung, Richard E Staub, Maria N Preobrazhenskaya, Leonard F Bjeldanes, Gary L Firestone
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 186 Issue 3 Pg. 255-66 (Aug 05 2010) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 20570586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Benzyl Compounds
• Estrogen Antagonists
• Estrogen Receptor alpha
• Indoles
• Sp1 Transcription Factor
• DNA
• indole-3-carbinol
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Anticarcinogenic Agents (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Benzyl Compounds (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Brassica (chemistry)
• Breast Neoplasms (drug therapy)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 6 (genetics, metabolism)
• DNA (metabolism)
• Estrogen Antagonists (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Mice
• Mice, Nude
• Sp1 Transcription Factor (metabolism)