Abstract 342: Telomerase-dependent oncolytic adenovirus sensitizes human osteosarcoma cells to chemotherapy through Mcl-1 downregulation

Abstract

Abstract Osteosarcoma is the most common malignant primary bone tumor. Despite advances in multi-agent chemotherapy, poor response to chemotherapy is one of the critical prognostic factors in osteosarcoma. Therefore, enhancement of chemosensitivity is one approach to improve the survival of osteosarcoma patients. We recently developed a telomerase-specific replication-competent oncolytic adenovirus, Telomelysin (OBP-301). A Phase I clinical trial in the U.S. showed the safety of OBP-301 in advanced cancer patients, and a Phase I/II clinical trial for malignant thoracic tumors is currently undergoing. We recently confirmed the antitumor effect of OBP-301 monotherapy in human osteosarcoma cells. In this study, we investigated the chemosensitizing effect of OBP-301 in human osteosarcoma cells and the molecular mechanism in the OBP-301-mediated enhancement of cell death. We used four human osteosarcoma cell lines, HOS, MNNG/HOS, 143B and SaOS-2. OBP-301 is an attenuated adenovirus, in which the hTERT promoter drives the expression of E1 gene, and causes tumor-selective lysis in a variety of human malignant tumor cells with telomerase activity. OBP-301 infection enhanced the cytotoxic effect of chemotherapeutic agents, cisplatin and doxorubicin, that are commonly used for the treatment of osteosarcomas. The calculation of combination index revealed the synergistic effects in all human osteosarcoma cell lines. Combination of OBP-301 increased apoptosis in the chemotherapeutic agents-treated cells. To clarify the molecular mechanism for the chemosensitizing effect of OBP-301, the expression of Bcl-2 family proteins, which are critical regulators of apoptosis, were investigated. In OBP-301-infected MNNG/HOS and SaOS-2 cells, the expression level of Mcl-1 was markedly decreased by OBP-301 infection. Downregulation of Mcl-1 expression by siRNA enhanced the chemotherapeutic agents-induced apoptosis. Moreover, combination therapy of chemotherapeutic agents with OBP-301 significantly suppressed tumor growth in a subcutaneous xenograft tumor model compared to monotherapy with chemotherapeutic agents or OBP-301. Anti-apoptotic Mcl-1 protein has been shown to be frequently overexpressed in human sarcomas. Overexpression of anti-apoptotic proteins is an important factor to prevent chemotherapy-induced apoptosis in cancer. We demonstrated the involvement of Mcl-1 suppression in the chemosensitizing effect of OBP-301 in human osteosarcoma cells. These results suggest that Mcl-1 is a critical target for improvement of the chemosensitivity in human osteosarcoma cells and the combination of chemotherapy with OBP-301 may be a novel therapeutic strategy for osteosarcoma patients. Citation Format: Shuhei Osaki, Toshinori Omori, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Tsuyoshi Sasaki, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara. Telomerase-dependent oncolytic adenovirus sensitizes human osteosarcoma cells to chemotherapy through Mcl-1 downregulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 342. doi:10.1158/1538-7445.AM2014-342