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- Title
PARP Inhibition Enhances the Anticancer Activity of Ruthenium(II) Polypyridyl Complex, [Ru(Dppz)2pip]<sup>2+</sup> in Lung Cancer Cells.
- Authors
Ahmad, Haslina; Yusoh, Nur Aininie; Lin Chia, Suet
- Abstract
Most ruthenium (II) polypyridyl complexes (RPC) have been designed to mimic platinumbased chemotherapyand in the last decades, several of them have been clinically studied as promising anticancer agents. In our previous study, we have demonstrated the role of [Ru(dppz)2PiP]2+(DPPZ:dipyridophenazine&PIP:2-phenylimidazo[4,5][1,10]phenantroline) or Ru-PIP installing the replication fork progressionleading to DNA double-strand breaks (DSBs). And in response to this DNA replication stress, DNA damage response (DDR) pathways are activated. PARP inhibitors (PARPi) are a part of DDR signalling and several of them have recently passed clinical trials and become FDA-approved chemotherapeutic drugs including olaparib. The present study is aimed to evaluate the use of the RPC; Ru-PIP in combination with olaparib as new therapeutic strategy. The cytotoxic effects of treatment with Ru-PIP and/orolaparibon A549 cells growth was determined by MTT assay and using the established method by Chou and Talalay, the combination indices (CI) were calculated to interpret the interactions between the two agents. A549 cellssurvival ability was investigated using clonogenic survival assay and the potential cytotoxicity mechanisms were assessed by cell cycle analysis and apoptosis assay. Herein, we reported that when used as single agents, both agents caused mild impact on A549 cells even after 72 h treatment. In addition, RuPIP was able to effectively synergize with olaparib in inducing growth inhibitory effect on A549 cells and synergy was further observed where almost a total loss in cells clonogenicity was observed when treated with Ru-PIP/olaparib combination. The selected synergistic combination was found to enhance G1/S cell cycle arrest and result an increase in apoptotic cell death in comparison to single agents alone. These results established that the ruthenium(II) polypyridyl metallo-intercalator, Ru-PIP showed potent synergy with PARP inhibitor olaparib in A549 cells and merit further investigation in pre-clinical and clinical studies with the potential to replace current platinum-chemotherapy for lung cancer treatment.
- Subjects
DNA repair; UNITED States. Food &; Drug Administration; DNA replication; POLY(ADP-ribose) polymerase; CANCER cells; LUNG cancer; RUTHENIUM; DOUBLE-strand DNA breaks
- Publication
Current Trends in Biotechnology & Pharmacy, 2020, p35
- ISSN
0973-8916
- Publication type
Article