TY - JOUR
T1 - Arresting cancer proliferation by small-molecule gene regulation
AU - Dickinson, Liliane A.
AU - Burnett, Ryan
AU - Melander, Christian
AU - Edelson, Benjamin S.
AU - Arora, Paramjit S.
AU - Dervan, Peter B.
AU - Gottesfeld, Joel M.
N1 - Funding Information:
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.
PY - 2004/11
Y1 - 2004/11
N2 - 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.
AB - 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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U2 - 10.1016/j.chembiol.2004.09.004
DO - 10.1016/j.chembiol.2004.09.004
M3 - Article
C2 - 15556009
AN - SCOPUS:8844273442
SN - 1074-5521
VL - 11
SP - 1583
EP - 1594
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 11
ER -