Synergistic antitumor effects of CDK inhibitor SNS-032 and an oncolytic adenovirus co-expressing TRAIL and Smac in pancreatic cancer

Abstract

Gene therapy using oncolytic adenoviruses is a novel approach for human cancer therapeutics. The current study aimed to investigate whether the combined use of an adenovirus expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and second mitochondria-derived activator of caspase (Smac) upon caspase activation (ZD55-TRAIL-IETD-Smac) and cyclin-dependent kinase (CDK) inhibitor SNS-032 will synergistically reinforce their anti-pancreatic cancer activities. The experiments in vitro demonstrated that SNS-032 enhances ZD55-TRAIL-IETD-Smac-induced apoptosis and causes marked pancreatic cancer cell death. Western blot assays suggested that the SNS-032 intensified ZD55-TRAIL-IETD-Smac-induced apoptosis of pancreatic cancer cells by affecting anti-apoptotic signaling elements, including CDK-2, CDK-9, Mcl-1 and XIAP. Additionally, animal experiments further confirmed that the combination of SNS-032 and ZD55-TRAIL-IETD-Smac significantly inhibited the growth of BxPC-3 pancreatic tumor xenografts. In conclusion, the present study demonstrated that SNS-032 sensitizes human pancreatic cancer cells to ZD55-TRAIL-IETD-Smac-induced cell death in vitro and in vivo. These findings indicate that combined treatment with SNS-032 and ZD55-TRAIL-IETD-Smac could represent a rational approach for anti-pancreatic cancer therapy.