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.

除了诱导对 PARP-1 的催化抑制外，PARP 抑制剂还可以在 DNA 损伤部位捕获 PARP 蛋白并形成有毒的 PARP-DNA 复合物。这些复合物阻碍 DNA 修复过程，导致癌细胞死亡。为了研究通过 PARP 捕获的抗癌作用的详细机制，我们用姜黄素 (Cur)、奥拉帕尼 (Ola) 及其组合 (Cur + Ola) 处理了口腔癌细胞 (H-357)。Cur + Ola 处理触发了 PARP-1 和腺瘤性息肉病大肠杆菌 (APC) 的表达，并下调了染色质部分中的其他碱基切除修复 (BER) 蛋白，但不在核部分中。Cur + Ola 处理抑制了 PARylation，改变了 PARP-1 与代表性 BER 蛋白的相互作用，并在 S 期阻止了细胞。我们首次提供了直接证据并测量了 Ola 在 Cur 预处理的 H-357 细胞中的细胞 PARP-1 捕获潜力。在 APC 沉默的 H-357 细胞中发现未改变的细胞 PARP-1 捕获、未改变的 BER 蛋白表达和 BER 活性，这进一步证实了 DNA 损伤/修复反应是 APC 依赖性的。有趣的是，在 Cur + Ola 处理的细胞的染色质中注意到染色质重塑物“在肝癌 1 中扩增”（ALC1）的完全消除，组蛋白 H3 和组蛋白乙酰转移酶（P300）的表达降低。它们的表达在 APC 沉默的细胞中保持不变。Cur + Ola 还改变了 ALC1 与包括 APC 在内的 BER 蛋白的相互作用。因此，