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Poly(ADP-ribose) polymerase inhibition enhances p53-dependent and -independent DNA damage responses induced by DNA damaging agent
| Content Provider | Scilit |
|---|---|
| Author | Nguyen, Diana Zajac-Kaye, Maria Rubinstein, Larry Voeller, Donna Tomaszewski, Joseph E. Kummar, Shivaani Chen, Alice P. Pommier, Yves Doroshow, James H. Yang, Sherry X. |
| Copyright Year | 2011 |
| Description | 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. |
| Related Links | https://www.tandfonline.com/doi/pdf/10.4161/cc.10.23.18170?needAccess=true https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272289/pdf https://www.landesbioscience.com/journals/cc/NguyenCC10-23.pdf |
| Ending Page | 4082 |
| Page Count | 9 |
| Starting Page | 4074 |
| ISSN | 15384101 |
| e-ISSN | 15514005 |
| DOI | 10.4161/cc.10.23.18170 |
| Journal | Cell Cycle |
| Issue Number | 23 |
| Volume Number | 10 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2011-12-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Cell Cycle Oncology Dna Damaging Agent G2 Arrest Microarray Parp Inhibition P53 Topotecan Veliparib (abt-888) |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Developmental Biology Medicine Molecular Biology |
