Abstract 4677: Tumor suppressor p53 reactivation by oncolytic adenovirus reverses chemoresistance in human osteosarcomas

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.4677-4677
• Main Authors: Sugiu, Kazuhisa, Tazawa, Hiroshi, Hasei, Joe, Osaki, Shuhei, Yamakawa, Yasuaki, Omori, Toshinori, Komatsubara, Tadashi, Uotani, Kouji, Fujiwara, Tomohiro, Kunisada, Toshiyuki, Urata, Yasuo, Ozaki, Toshifumi, Fujiwara, Toshiyoshi
• Format: Article
• Language: English
• Subjects: Adenoviridae
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-4677

Background: Osteosarcoma is a primary malignant bone tumor. Despite recent advances in multi-agent chemotherapy and aggressive surgical resection, the poor response to chemotherapy often contributes to poor prognosis in osteosarcoma patients. Therefore, the development of novel strategies for reversing the chemoresistance is a pivotal approach to improve the clinical outcome for osteosarcoma patients. We recently developed a tumor suppressor p53-expressing oncolytic adenovirus, OBP-702, which drives the adenoviral E1 gene under the control of the human telomerase reverse transcriptase promoter for tumor-specific virus replication and induces profound p53 expression for tumor-specific cell death. We recently found that OBP-702 effectively kills human osteosarcoma cells. In this study, we investigated the therapeutic potential of OBP-702 as a chemosensitizing reagent in human osteosarcoma cells with different p53 status. Methods: We used 4 human osteosarcoma cell lines with different p53 status, including U2OS (p53 wild-type), MNNG/HOS (p53 mutant), 143B (p53 mutant), SaOS2 (p53 null). We also used the doxorubicin (DOX)-resistant U2OS cells, which were established by sequential exposure to DOX over 3 months. We performed the XTT assay to examine the antitumor effects of DOX and OBP-702. Combination efficacy between DOX and OBP-702 was assessed by calculating the combination index using CalcuSyn software (BioSoft, Inc.). We further investigated the DOX- and OBP-702-mediated apoptosis in parental and DOX-resistant U2OS cells using Western blot analysis. Results: OBP-702 improved the sensitivity to DOX in a dose-dependent manner in all 4 osteosarcoma cell lines. The calculation of combination index revealed the synergistic effect in all 4 osteosarcoma cell lines. Combination with DOX and OBP-702 induced more profound apoptosis than monotherapy in all 4 osteosarcoma cell lines. Moreover, in DOX-resistant U2OS cells, OBP-702 induced the cytopathic effect as well as parental U2OS cells. Synergistic effect was also observed in DOX-resistant U2OS cells when we treated with DOX and OBP-702. Although DOX-resistant U2OS cells was more resistant to the DOX-mediated apoptosis than parental cells, OBP-702 enhanced the DOX-mediated apoptosis in DOX-resistant U2OS cells as well as parental cells. Conclusions: These results suggest that OBP-702-mediated p53 reactivation reverses the chemoresistance in human osteosarcomas. Citation Format: Kazuhisa Sugiu, Hiroshi Tazawa, Joe