Arresting cancer proliferation by small-molecule gene regulation

Liliane A. Dickinson, Ryan Burnett, Christian Melander, Benjamin S. Edelson, Paramjit Arora, Peter B. Dervan, Joel M. Gottesfeld

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1583-1594
Number of pages12
JournalChemistry and Biology
Volume11
Issue number11
DOIs
StatePublished - Nov 2004

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Gene expression
Nylons
Cells
Molecules
Genes
Chlorambucil
Tumors
Cell Line
Neoplasms
Polymerase Chain Reaction
Pyrroles
Alkylating Agents
Alkylation
Microarray Analysis
Growth
Nude Mice
Histones
Small Interfering RNA
Cell Cycle
Colon

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Dickinson, L. A., Burnett, R., Melander, C., Edelson, B. S., Arora, P., Dervan, P. B., & Gottesfeld, J. M. (2004). Arresting cancer proliferation by small-molecule gene regulation. Chemistry and Biology, 11(11), 1583-1594. https://doi.org/10.1016/j.chembiol.2004.09.004

Arresting cancer proliferation by small-molecule gene regulation. / Dickinson, Liliane A.; Burnett, Ryan; Melander, Christian; Edelson, Benjamin S.; Arora, Paramjit; Dervan, Peter B.; Gottesfeld, Joel M.

In: Chemistry and Biology, Vol. 11, No. 11, 11.2004, p. 1583-1594.

Research output: Contribution to journalArticle

Dickinson, LA, Burnett, R, Melander, C, Edelson, BS, Arora, P, Dervan, PB & Gottesfeld, JM 2004, 'Arresting cancer proliferation by small-molecule gene regulation', Chemistry and Biology, vol. 11, no. 11, pp. 1583-1594. https://doi.org/10.1016/j.chembiol.2004.09.004
Dickinson LA, Burnett R, Melander C, Edelson BS, Arora P, Dervan PB et al. Arresting cancer proliferation by small-molecule gene regulation. Chemistry and Biology. 2004 Nov;11(11):1583-1594. https://doi.org/10.1016/j.chembiol.2004.09.004
Dickinson, Liliane A. ; Burnett, Ryan ; Melander, Christian ; Edelson, Benjamin S. ; Arora, Paramjit ; Dervan, Peter B. ; Gottesfeld, Joel M. / Arresting cancer proliferation by small-molecule gene regulation. In: Chemistry and Biology. 2004 ; Vol. 11, No. 11. pp. 1583-1594.
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