Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 186, Issue 3, Pages 255-266Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2010.05.015
Keywords
Indole-3-carbinol; 1-Benzyl-indole-3-carbinol; Breast cancer cells; Anti-proliferative signaling; Disrupted estrogen receptor responsiveness; High potency indole derivatives
Funding
- National Cancer Institute [CA102360]
- Susan G. Komen Breast Cancer Fund
- California Breast Cancer Research Program [13GB-1801]
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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 IC50 of 52 mu M, and 1-benzyl-I3C IC50 of 0.05 mu M). At significantly lower concentrations, 1-benzyl-I3C induced a robust Cl 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. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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