A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts

PLoS One. 2014 Jun 27;9(6):e100993. doi: 10.1371/journal.pone.0100993. eCollection 2014.

Abstract

The homologous recombination pathway is responsible for the repair of DNA double strand breaks. RAD51, a key homologous recombination protein, promotes the search for homology and DNA strand exchange between homologous DNA molecules. RAD51 is overexpressed in a variety of cancer cells. Downregulation of RAD51 by siRNA increases radio- or chemo-sensitivity of cancer cells. We recently developed a specific RAD51 small molecule inhibitor, B02, which inhibits DNA strand exchange activity of RAD51 in vitro. In this study, we used human breast cancer cells MDA-MB-231 to investigate the ability of B02 to inhibit RAD51 and to potentiate an anti-cancer effect of chemotherapeutic agents including doxorubicin, etoposide, topotecan, and cisplatin. We found that the combination of B02 with cisplatin has the strongest killing effect on the cancer cells. We then tested the effect of B02 and cisplatin on the MDA-MB-231 cell proliferation in mouse xenografts. Our results showed that B02 significantly enhances the therapeutic effect of cisplatin on tumor cells in vivo. Our current data demonstrate that use of RAD51-specific small molecule inhibitor represents a feasible strategy of a combination anti-cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Quinazolinones / pharmacology*
  • Quinazolinones / therapeutic use
  • Rad51 Recombinase / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays

Substances

  • (E)-3-benzyl-2-(2-(pyridin-3-yl) vinyl) quinazolin-4(3H)-one
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Quinazolinones
  • Doxorubicin
  • Rad51 Recombinase
  • Cisplatin