N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells.

N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Research Abstract Details 

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N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Abstract Text:

Sarah M Jump,Jenny Kung,Richard Staub,Matthew A Kinseth,Erin J Cram,Larisa N Yudina,Maria N Preobrazhenskaya,Leonard F Bjeldanes,Gary L Firestone,Sarah M Jump,Jenny Kung,Richard Staub,Matthew A Kinseth,Erin J Cram,Larisa N Yudina,Maria N Preobrazhenskaya,Leonard F Bjeldanes,Gary L Firestone,

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as cabbage, broccoli, and Brussels sprouts, induces a G1 cell cycle arrest of human breast cancer cells. Structure-activity relationships of I3C that mediate this anti-proliferative response were investigated using synthetic and natural I3C derivatives that contain substitutions at the indole nitrogen. Nitrogen substitutions included N-alkoxy substituents of one to four carbons in length, which inhibit dehydration and the formation of the reactive indolenine. Analysis of growth and cell cycle arrest of indole-treated human breast cancer cells revealed a striking increase in efficacy of the N-alkoxy I3C derivatives that is significantly enhanced by the presence of increasing carbon lengths of the N-alkoxy substituents. Compared to I3C, the half maximal growth arrest responses occurred at 23-fold lower indole concentration for N-methoxy I3C, 50-fold lower concentration for N-ethoxy I3C, 217-fold lower concentration for N-propoxy I3C, and 470-fold lower concentration for N-butoxy I3C. At these lower concentrations, each of the N-alkoxy substituted compounds induced the characteristic I3C response in that CDK6 gene expression, CDK6 promoter activity, and CDK2 specific enzymatic activity for its retinoblastoma protein substrate were strongly down regulated. 3-Methoxymethylindole and 3-ethoxymethylindole were approximately as bioactive as I3C, whereas both tryptophol and melatonin failed to induce the cell cycle arrest, showing the importance of the C-3 hydroxy methyl substituent on the indole ring. Taken together, our study establishes the first I3C structure-activity relationship for cytostatic activities, and implicates I3C-based N-alkoxy derivatives as a novel class of potentially more potent experimental therapeutics for breast cancer.

N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Publishing Authors By Initials

SM Jump,J Kung,R Staub,MA Kinseth,EJ Cram,LN Yudina,MN Preobrazhenskaya,LF Bjeldanes,GL Firestone,SM Jump,J Kung,R Staub,MA Kinseth,EJ Cram,LN Yudina,MN Preobrazhenskaya,LF Bjeldanes,GL Firestone,

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N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Biochemical pharmacology

VOLUME: 75

Page Numbers: 713-24

Journal Abbreviation: Biochem. Pharmacol.

ISSN: 0006-2952

DAY: 2

MONTH: 10

YEAR: 2007

N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Information

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LANGUAGE: eng

NlmUniqueID: 101032

N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Keywords Mesh Terms:

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Grant and Affiliation Information for N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells.

AFFILIATION: Department of Molecular and Cell Biology and The Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720-3200, United States.

Country: England

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MEDLINETA: Biochem Pharmacol

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