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: 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
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 10 Issue 23 Pg. 4074-82 (Dec 01 2011) ISSN: 1551-4005 [Electronic] United States
• PMID: 22101337 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzimidazoles
• Cyclin-Dependent Kinase Inhibitor p21
• Poly(ADP-ribose) Polymerase Inhibitors
• Tumor Suppressor Protein p53
• veliparib
• 7-hydroxystaurosporine
• Topotecan
• Poly(ADP-ribose) Polymerases
• Staurosporine

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzimidazoles (pharmacology)
• Cell Cycle Checkpoints
• Cell Death
• Cyclin-Dependent Kinase Inhibitor p21 (antagonists & inhibitors, genetics, metabolism)
• DNA Damage
• DNA Repair
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• HT29 Cells
• Humans
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Signal Transduction
• Staurosporine (analogs & derivatives, pharmacology)
• Time Factors
• Topotecan (pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)