Arresting cancer proliferation by small-molecule gene regulation
Abstract
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.
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, http://dx.doi.org/10.1016/j.chembiol.2006.02.006. (http://www.sciencedirect.com/science/article/pii/S1074552106000767)Attached Files
Supplemental Material - mmc1.pdf
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Additional details
- Eprint ID
- 66767
- Resolver ID
- CaltechAUTHORS:20160509-114909681
- Howard Hughes Medical Institute (HHMI)
- NIH Postdoctoral ellowship
- T32 A107354
- Created
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2016-05-17Created from EPrint's datestamp field
- Updated
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2023-06-01Created from EPrint's last_modified field