Base Excision Repair Inhibition by Methoxyamine Impairs Growth and Sensitizes Osteosarcoma Cells to Conventional Treatments

摘要

The outcome of patients with osteosarcoma has not significantly improved in the last three decades. Therefore, there is still a need for the development of more effective therapeutic strategies. Methoxyamine (MX) is a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing a variety of tumor cells to ionizing radiation and chemotherapeutic drugs. In the present study, the in vitro antiproliferative effects of MX were evaluated in two osteosarcoma cell lines, HOS and MG-63. Evaluation of the influence on radiosensitivity and drug interactions in simultaneous treatments with methotrexate, doxorubicin, and cisplatin was also performed. Exposure to MX significantly decreased cell proliferation and mediated a substantial increase of apoptosis. Moreover, our results showed that MX synergized with ionizing radiation in both cell lines while potentiated the antitumor effects of cisplatin and methotrexate. Altogether, the results presented herein demonstrate the feasibility of inhibiting the BER pathway, which may in future be a promising strategy for overcoming intrinsic tumor resistance and to improve the outcome of patients with osteosarcoma.