PARP inhibitor Olaparib Enhances the Apoptotic Potentiality of Curcumin by Increasing the DNA Damage in Oral Cancer Cells through Inhibition of BER Cascade.

Abstract

Although Olaparib (Ola, a PARP-inhibitor), in combination with other chemotherapeutic agents, was clinically approved to treat prostate cancer, but cytotoxicity, off-target effects of DNA damaging agents limit its applications in clinic. To improve the anti-cancer activity and to study the detailed mechanism of anti-cancer action, here we have used bioactive compound curcumin (Cur) in combination with Ola. Incubation of Ola in Cur pre-treated cells synergistically increased the death of oral cancer cells at much lower concentrations than individual optimum dose and inhibited the topoisomerase activity. Short exposure of Cur caused DNA damage in cells, but more increased DNA damage was noticed when Ola has incubated in Cur pre-treated cells. This combination did not alter the major components of homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways but significantly altered both short patch (SP) and long patch (LP) base excision repair (BER) components in cancer cells. Significant reduction in relative luciferase activity, expression of BER components and PARylation after Cur and Ola treatment confirmed this combination inhibit the BER activity in cells. Reduction of PARylation, decreased expression of BER components, decreased tumor volume and induction of apoptosis were also noticed in Cur + Ola treated Xenograft mice model. The combination treatment of Cur and Ola also helped in recovering the body weight of tumor-bearing mice. Thus, Cur + Ola combination increased the oral cancer cells death by not only causing the DNA damage but also blocking the induction of BER activity.