New insights into PARP inhibitors' effect on cell cycle and homology-directed DNA damage repair Journal Article
| Authors: | Jelinic, P.; Levine, D. A. |
| Article Title: | New insights into PARP inhibitors' effect on cell cycle and homology-directed DNA damage repair |
| Abstract: | In preclinical and clinical studies, olaparib and veliparib are the most represented PARP inhibitors (PARPi), which mainly target homologous DNA damage repair pathway-deficient cancer cells. Their off-target effects are not fully understood, especially with regard to cell cycle and homology-directedDNA damage repair. Our objective was to comparatively evaluate olaparib and veliparib in this context and correlate our findings with their therapeutic potential. We used a well-established direct repeat GFP (DR-GFP) reporter assay in U2O SDR-GFP and H1299DR-GFP cells and measured DNA damage repair activity upon drug treatment. Olaparib-treated U2OSDR-GFP cells showed a dramatic decrease in DNA damage repair versus veliparib irrespective of inhibitory potency. We demonstrate that this effect was a result of olaparib's strong effect on the cell cycle. Unlike in veliparib-treated U2OSDR-GFP cells, in olaparib-treated cells S-phase decreased and G2-phase increased sharply, indicating a G2-phase arrest-like state and replicative stress. This was further confirmed by upregulation of p53 and p21 and accumulation of cyclin A. Lack of the same effect in p53-null H1299 DR-GFP cells suggested that olaparib's effect is p53 related, which was confirmed in p53-depleted U2OSDR-GFP and p53-null HCT116 cells. Importantly, we also demonstrate that olaparib, but not veliparib, induced a robust phosphorylation of Chk1, a crucial component of the replicative stress response pathway. Our data show olaparib and veliparib differ in their off-target effects; olaparib, unlike veliparib, mitigates DNA damage repair activity via G2 cell-cycle arrest-like effect in a p53-dependent manner. These off-target effects may add to PARPis' anticancer properties. ©2014 AACR. |
| Journal Title: | Molecular Cancer Therapeutics |
| Volume: | 13 |
| Issue: | 6 |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-06-01 |
| Start Page: | 1645 |
| End Page: | 1654 |
| Language: | English |
| DOI: | 10.1158/1535-7163.mct-13-0906-t |
| PROVIDER: | scopus |
| PUBMED: | 24694947 |
| DOI/URL: | |
| Notes: | Mol. Cancer Ther. -- Export Date: 8 July 2014 -- CODEN: MCTOC -- Source: Scopus |
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