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Arresting cancer proliferation by small-molecule gene regulation

Dickinson, Liliane A. and Burnett, Ryan and Melander, Christian and Edelson, Benjamin S. and Arora, Paramjit S. and Dervan, Peter B. and Gottesfeld, Joel M. (2004) Arresting cancer proliferation by small-molecule gene regulation. Chemistry and Biology, 11 (11). pp. 1583-1594. ISSN 1074-5521.

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A small library of pyrrole-imidazole polyamide-DNA alkylator (chlorambucil) conjugates was screened for effects on morphology and growth characteristics of a human colon carcinoma cell line, and a compound was identified that causes cells to arrest in the G2/M stage of the cell cycle. Microarray analysis indicates that the histone H4c gene is significantly downregulated by this polyamide. RT-PCR and Western blotting experiments confirm this result, and siRNA to H4c mRNA yields the same cellular response. Strikingly, reduction of H4 protein by >50% does not lead to widespread changes in global gene expression. Sequence-specific alkylation within the coding region of the H4c gene in cell culture was confirmed by LM-PCR. The compound is active in a wide range of cancer cell lines, and treated cells do not form tumors in nude mice. The compound is also active in vivo, blocking tumor growth in mice, without obvious animal toxicity.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2004 Elsevier. Received: August 4, 2004; Revised: September 3, 2004; Accepted: September 9, 2004; Published: November 29, 2004. We thank Peter Vogt, Ernest Beutler, and Thomas Dueul for discussions and advice; Steve Head and members of the Scripps Microarray Core facility for assistance with gene profiling studies; Malcolm Wood for help with deconvolution microscopy; Daniel Salomon for access to human microarray data; Caren Lund for FACS analysis; and Veronique Blais and David Alvarez for microscopy. This work was supported by grants from the National Institutes of Health. B.S.E. was supported by a predoctoral fellowship from the Howard Hughes Medical Institute, and R.B. was supported by National Institute of Health postdoctoral training grant T32 AI07354. J.M.G. and P.B.D. dedicate this work to the memory of Francis Crick.
Errata:Liliane A. Dickinson, Ryan Burnett, Christian Melander, Benjamin S. Edelson, Paramjit S. Arora, Peter B. Dervan, Joel M. Gottesfeld, Arresting Cancer Proliferation by Small-Molecule Gene Regulation, Chemistry & Biology, Volume 13, Issue 3, March 2006, Page 339, ISSN 1074-5521, (
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Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Postdoctoral ellowshipT32 A107354
Issue or Number:11
Record Number:CaltechAUTHORS:20160509-114909681
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66767
Deposited By: Victoria Brennan
Deposited On:17 May 2016 20:21
Last Modified:26 Nov 2019 11:15

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