Abstract
Abstract Osteosarcoma is a rare highly malignant tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The enhancement of chemosensitivity is a potential approach to improve the prognostic outcome of osteosarcoma patients. We developed a telomerase-specific replication-competent oncolytic adenovirus, OBP-301. We recently confirmed the antitumor effect of OBP-301 monotherapy in human osteosarcoma cells. We also revealed the synergistic chemosensitizing effect of OBP-301 in human epithelial malignant tumor cells. In this study, we investigated the chemosensitizing effect of OBP-301 and its underlying mechanisms in human osteosarcoma cells. We used four human osteosarcoma cell lines, SaOS-2, MNNG/HOS, HOS and 143B. 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). The calculation of combination index revealed the synergistic effects in all four human osteosarcoma cell lines. Combination of OBP-301 increased chemotherapy-induced apoptosis. To clarify the molecular mechanism underlying the chemosensitizing effect of OBP-301, we investigated whether OBP-301 affects the expression of anti-apoptotic BCL2 family proteins. In SaOS-2 and MNNG/HOS cells, the expression level of MCL1 was markedly decreased by OBP-301 infection. MCL1 knockdown by siRNA enhanced the chemotherapy-induced apoptosis as well as OBP-301. We recently revealed that OBP-301 increase the expression of cellular miRNAs in human cancer cells. To investigate the underlying mechanism of OBP-301-mediated MCL1 suppression, we determined whether OBP-301 upregulates MCL1-targeted miRNAs. OBP-301 dose-dependently upregulated the expression of MCL1 targeted miR-29 in SaOS-2 and MNNG/HOS cells. Exogenously introduced miR-29 efficiently suppressed MCL1 expression and enhanced the chemotherapy-induced apoptosis. Moreover, combination treatment significantly inhibited tumor growth, as compared to monotherapy, in a subcutaneous xenograft tumor model. MCL1 is overexpressed in various types of human tumor cells. Overexpression of anti-apoptotic proteins is an important factor to prevent chemotherapy-induced apoptosis in cancer. We demonstrated OBP-301 efficiently kills human osteosarcoma cells and markedly sensitizes them to chemotherapy. MCL1 suppression via OBP-301-induced miR-29 is critical as the underlying mechanism of the OBP-301 mediated chemosensitizing effect. These results suggest that replicative virus-mediated tumor specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients. Citation Format: Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara. Chemosensitizing effect of telomerase-dependent oncolytic adenovirus through virally induced microRNA-29-mediated MCL1 downregulation in osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4299. doi:10.1158/1538-7445.AM2017-4299
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