The efficacy of combination therapy using adeno-associated virus-TRAIL targeting to telomerase activity and cisplatin in a mice model of hepatocellular carcinoma

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) functions as a soluble cytokine and has been demonstrated significant antitumor activity against a variety of cancer cell lines without toxicity to most normal cells. Cisplatin is a potent anticancer agent and is widely used in the clinical for treatment of human cancers. Adeno-associated virus (AAV2) is a promising gene delivery vehicle for its advantage of low pathogenicity and long-term gene expression. However, lack of tissue specificity caused low efficiency of AAV transfer to target cells. The promoter of human telomerase reverse transcriptase (hTERT) is a good candidate to enhance targeting efficiency of AAV in cancer cells. Although AAV-mediated TRAIL controlled by hTERT promoter (AAV-hTERT-TRAIL) has obvious antitumor activity, the tumor cannot be completely eradicated. In this study, we first examined the effectiveness of combination therapy of cisplatin and AAV-hTERT-TRAIL on human hepatocellular carcinoma (HCC) in vitro and in vivo. For in vitro experiments, tumor cell lines were treated with cisplatin, virus, or both. The transgene TRAIL expression controlled by hTERT promoter was evaluated in BEL7404 HCC cell line. Cytotoxicity was performed by MTT analysis. Cell apoptosis was detected by flow cytometry analysis. The in vivo antitumor efficacy of combination treatment with cisplatin and AAV-hTERT-TRAIL was assessed in human hepatocellular carcinoma xenografts mouse model. The enhanced TRAIL expression was observed in BEL7404 cells treated with AAV-hTERT-TRAIL plus cisplatin. Treatment with both AAV-hTERT-TRAIL and cisplatin exhibited stronger cytotoxicity and induced more significant apoptosis in cancer cells compared with AAV-hTERT-TRAIL or cisplatin alone, respectively. Moreover, in animal experiments, the combined treatment greatly suppressed tumor growth and resulted in tumor cell death. AAV-mediated therapeutic gene expression in combination with chemotherapy provides a promising therapeutic strategy for human cancers. These data suggest that combined use of AAV-hTERT-TRAIL and cisplatin may have potential clinical application.