Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent

Diana Nguyen, Maria Zajac-Kaye, Larry Rubinstein, Donna Voeller, Joseph E. Tomaszewski, Shivaani Kummar, Alice P. Chen, Yves Pommier, James H. Doroshow, Sherry X. Yang

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Targeting DNA repair with poly(ADP-ribose) polymerase (PA RP) inhibitors has shown a broad range of anti-tumor activity in patients with advanced malignancies with and without BRCA deficiency. It remains unclear what role p53 plays in response to PA RP inhibition in BRCA-proficient cancer cells treated with DNA damaging agents. Using gene expression microarray analysis, we find that DNA damage response (DDR) pathways elicited by veliparib (ABT-888), a PA RP inhibitor, plus topotecan comprise the G1/S checkpoint, ATM and p53 signaling pathways in p53-wild-type cancer cell lines and BRCA1, BRCA2 and ATR pathway in p53-mutant lines. In contrast, topotecan alone induces the G 1/S checkpoint pathway in p53 wild-type lines and not in p53-mutant cells. These responses are coupled with G2/G1 checkpoint effectors p21CDKN1A upregulation, and Chk1 and Chk2 activation. The drug combination enhances G2 cell cycle arrest, apoptosis and a marked increase in cell death relative to topotecan alone in p53-wild-type and p53-mutant or -null cells. We also show that the checkpoint kinase inhibitor UCN-01 abolishes the G2 arrest induced by the veliparib and topotecan combination and further increases cell death in both p53-wild-type and -mutant cells. Collectively, PA RP inhibition by veliparib enhances DDR and cell death in BRCA-proficient cancer cells in a p53-dependent and -independent fashion. Abrogating the cell cycle arrest induced by PA RP inhibition plus chemotherapeutics may be a strategy in the treatment of BRCA-proficient cancer.

Original languageEnglish (US)
Pages (from-to)4074-4082
Number of pages9
JournalCell Cycle
Volume10
Issue number23
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

Keywords

  • DNA damaging agent
  • Microarray
  • P53
  • Parp inhibition
  • Topotecan
  • Veliparib (ABT-888)

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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