Sirtuin 1 and 2 inhibitors enhance the inhibitory effect of sorafenib in hepatocellular carcinoma cells

Multidrug resistance (MDR) counteracts the efficiency of sorafenib, an important first-line therapy for hepatocellular carcinoma (HCC). Sirtuins (SIRTs) 1 and 2 are associated with tumor progression MDR. We treated 2D 3D cultures (which mimic features in vivo tumors) from HCC cells sorafenib alone or presence SIRTs inhibitors (cambinol EX-527; combined treatments). Cultures subjected to treatments showed a greater fall cellular viability, proliferation (PCNA, cyclin D1 Ki-67 expression cell cycle analysis), migration invasion when compared only sorafenib. Similarly, produced more apoptosis (annexin V/PI, caspase-3/7 activity) than alone. Since dysregulation apoptotic blockage reported mechanisms MDR, modulation found PCNA, D1, proteins by cambinol EX-527 probably playing role enhancing sensitivity lines reduced MRP3 BCRP sorafenib-treated cells. ABC transporters contribute could be also influencing response Overall, behave similarly except that were less sensitive treatments, reinforcing clinical relevance current study. Findings presented this manuscript support potential application since we demonstrated these compounds enhance inhibitory effect upon treatment lines.