Arresting Cancer Cell Proliferation by Chemical Gene Regulation

Pyrrole-imidazole polyamides are a class of programmable small molecules that bind a broad spectrum of DNA sequences, and target sites in chromosomal DNA in the eukaryotic cell nucleus. A specific polyamide-DNA alkylator (chlorambucil) conjugate has been identified that blocks cancer cell growth by direct binding to one member of the human histone H4 gene family in cellular chromatin, resulting in down regulation of histone H4 mRNA synthesis.  The polyamide-alkylator is active in vivo, blocking cancer proliferation in a model for human colon cancer. The cover shows a fluorescent analogue of the polyamide staining the nucleus of a colon cancer cell.  Surrounding the cell nucleus are molecular models of the nucleosome and the polyamide-chlorambucil conjugate, with the DNA in white, the histone proteins in blue (H2A, H2B, H3) or green (H4), and the polyamide in yellow. Art by Ryan Burnett.