title: 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.affiliation: Department of Molecular and Cell Biology and The Cancer Research Laboratory, Univ. of California at Berkeley, Berkeley, CA 94720-3200, United States.
authors.forename: Hanh H
authors.initials: HH
authors.lastname: Nguyen
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Lavrenov
authors.forename: Shyam N
authors.initials: SN
authors.lastname: Sundar
authors.forename: David H H
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Min
authors.initials: M
authors.lastname: Tseng
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Marconett
authors.forename: Jenny
authors.initials: J
authors.lastname: Kung
authors.forename: Richard E
authors.initials: RE
authors.lastname: Staub
authors.forename: Maria N
authors.initials: MN
authors.lastname: Preobrazhenskaya
authors.forename: Leonard F
authors.initials: LF
authors.lastname: Bjeldanes
authors.forename: Gary L
authors.initials: GL
authors.lastname: Firestone
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001937:Brassica / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D001593:Benzyl Compounds; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D007211:Indoles; D016329:Sp1 Transcription Factor; D004247:DNA; C016517:indole-3-carbinol; D051361:Cyclin-Dependent Kinase 6