SurvivinT34A increases the therapeutic efficacy of arsenic trioxide in mouse hepatocellular carcinoma models

Abstract

Arsenic trioxide (ATO) has demonstrated clinical efficacy in acute promyelocytic leukemia (APL) and in vitro activity in various solid tumors. As2O3 as single agent exhibits poor efficacy for treatment of hepatocellular carcinoma (HCC) in phase II trial, suggesting that new modalities of treatment with enhanced therapeutic effect and alleviated toxicity are needed for application of As2O3 on patients with HCC. Survivin is the strongest inhibitor of apoptosis protein overexpressed in tumors, which has been proposed as an attractive target for new anticancer interventions. Disruption of survivin by the plasmid encoding the phosphorylation-defective mouse survivin threonine 34alanine mutant (Msurvivin T34A plasmid) has proved a promising strategy for suppressing a variety of murine cancer. In the present study, we attempted to test Msurvivin T34A and arsenic trioxide (ATO) on a cell line and mice bearing subcutaneous tumors, with regard to their effects and mechanisms. We observed that the co-treatment with surivinT34A and ATO significantly enhanced the antitumor activity by induction of apoptosis in Hepa1-6 tumor cells in vitro, compared with control groups. The synergistic apoptosis-inducing effect of combination of these two drugs resulted in elevation of reactive oxygen species (ROS) level which could be antagonized by the antioxidant N-acetyl-lcysteine. The combination treatment induced ROS-dependent collapse of the mitochondrial membrane potential. Moreover, the tumor growth in vivo was also remarkably inhibited by combination of surivinT34A and ATO when compared with control groups. Our findings demonstrate that the combination of surivinT34A and ATO exerted synergistic antitumor effects, providing a new perspective for clinical treatment of HCC.