In Vitro Cytotoxicity and Zebrafish Embryos Acute Toxicity Assessment of Ruthenium (II) Metal-based Complexes in Combination with PARP inhibitor.

Introduction: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) target the key DNA repair enzymes of PARP and have emerged as small molecule drugs. Recently, ruthenium(II) polypyridyl complexes (RPCs) have shown promise as anticancer candidates due to their ability to form non-covalent (reversible) interactions with DNA. Previously, we have reported the RPC [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = 2-(phenyl)-imidazo[ 4,5-f][1,10]phenanthroline), "Ru-PIP" induce replication stress in cancer cells by stalling the DNA replication fork progression. Therefore, the rational combination of Ru-PIP with PARPi may show synergistic activities in cancer cells. In the present study, we examine the combination of Ru-PIP with the most successful PARPi to date, Olaparib for synergy in lung cancer cells. We additionally assess toxicity of the identified combination in a zebrafish embryo model. Methods: A549 cells were treated with Ru-PIP or Olaparib single agents alone or in combination and MTT assay was carried out. Synergy was determined using Chou and Talalay combination index (CI) method in which C1 < 1 represents synergy and synergy was further confirmed using clonogenic survival assay. Further acute toxicity test of the identified synergy combination on zebrafish embryos was then carried out. Results: Ru-PIP and Olaparib synergy was observed in A549 lung cancer cell line. Synergy was confirmed by loss in clonogenic potential. Moreover, acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP. Conclusion: We demonstrate that the identified synergistic Ru-PIP/Olaparib combination may potentially reduce side effects observed in single-agent therapy and thus, demonstrate new promising therapeutic strategy to combat cancer. [ABSTRACT FROM AUTHOR]