title: Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent.
abstract: Targeting DNA repair with poly(ADP-ribose) polymerase (PARP) 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 PARP 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 PARP inhibitor, plus topotecan comprise the G1/S checkpoint, ATM, and p53 signaling pathways in p53-wildtype cancer cell lines and BRCA1, BRCA2 and ATR pathway in p53-mutant lines. In contrast, topotecan alone induces the G1/S checkpoint pathway in p53-wildtype lines and not in p53-mutant cells. These responses are coupled with G2/G1 checkpoint effectors p21(CDKN1A) 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-wildtype 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-wildtype and -mutant cells. Collectively, PARP 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 PARP inhibition plus chemotherapeutics may be a strategy in the treatment of BRCA-proficient cancer.
authors.affiliation: Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Nguyen
authors.forename: Maria
authors.initials: M
authors.lastname: Zajac-Kaye
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.forename: Donna
authors.initials: D
authors.lastname: Voeller
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Sherry X
authors.initials: SX
authors.lastname: Yang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D016923:Cell Death; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D019772:Topotecan / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016159:Tumor Suppressor Protein p53; C521013:veliparib; C054852:7-hydroxystaurosporine; D019772:Topotecan; D011065:Poly(ADP-ribose) Polymerases; D019311:Staurosporine
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