Arresting cancer proliferation by small-molecule gene regulation

Chem Biol. 2004 Nov;11(11):1583-94. doi: 10.1016/j.chembiol.2004.09.004.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Alkylating / chemistry
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Cell Line, Tumor
  • Cell Nucleus / chemistry
  • Cell Nucleus / drug effects
  • Cell Proliferation / drug effects
  • Chlorambucil / chemistry
  • Chlorambucil / pharmacology*
  • Cross-Linking Reagents / pharmacology
  • DNA / metabolism
  • Drug Evaluation, Preclinical
  • Gene Expression / drug effects*
  • Gene Expression Regulation
  • Gene Silencing
  • Gene Targeting
  • Histones / genetics
  • Humans
  • Nylons / chemistry
  • Nylons / pharmacology*


  • Antineoplastic Agents, Alkylating
  • Cross-Linking Reagents
  • Histones
  • Nylons
  • Chlorambucil
  • DNA