Olaparib enhances curcumin-mediated apoptosis in oral cancer cells by inducing PARP trapping through modulation of BER and chromatin assembly.

Apart from inducing catalytic inhibition of PARP-1, PARP inhibitors can also trap PARP proteins at the sites of DNA damage and forming toxic PARP-DNA complexes. These complexes obstruct the DNA repair process, resulting in cancer cell death. To study the detailed mechanism of anti-cancer action through PARP trapping, we have treated oral cancer cells (H-357) with curcumin (Cur), olaparib (Ola) and their combination (Cur + Ola). Cur + Ola treatment triggered the expressions of PARP-1 and adenomatous polyposis coli (APC) and down regulated other base excision repair (BER) proteins in the chromatin fraction but not in the nuclear fraction. Cur + Ola treatment inhibited PARylation, altered interaction of PARP-1 with representative BER proteins and arrested cells in S-phase. We have for the first time provided direct evidence and measured the cellular PARP-1 trapping potentiality of Ola in Cur pretreated H-357 cells. Unchanged cellular PARP-1 trapping, unaltered expression of BER proteins and BER activity were found in APC silenced H-357 cells, which further confirmed that the DNA damage/repair response was APC-dependent. Interestingly, complete abolishment of the chromatin remodeler 'amplified in Liver Cancer 1' (ALC1), decreased expression of Histone H3 and histone acetyltransferase (P300) was noted in chromatin of Cur + Ola treated cells. Their expressions remained unchanged in APC silenced cells. Cur + Ola also altered the interaction of ALC1 with BER proteins including APC. Thus, the present study reveals that Cur + Ola treatment increased oral cancer cell death not only through catalytic inhibition of PARP-1 but also predominantly through PARP-1 trapping and indirect inhibition of chromatin remodeling.