Doxorubicin (DOX) is one of the widely used chemotherapeutic drugs for the treatment of human osteosarcoma (OS). However, acquisition of DOX resistance is common in patients with OS, leading to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in OS primary tumors compared to paired normal tissue. In addition, survivin expression was further increased in DOX resistant cells (MG63/DOX) as compared to its parent cells (MG63). Thus, we hypothesize that targeting of survivin in OS could reverse the DOX resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of DOX. We test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with DOX in vitro and in vivo. We found that combination treatment of YM155 and DOX in DOX resistant cells (MG63/DOX) could significantly inhibited cell proliferation and colony formation, induce cell apoptosis and promoted caspase-3, -8, and -9 activity in vitro, and promoted tumor regression in established OS xenograft models. Taken together, the evidence presented here supports the favorable preclinical evaluation that YM155 could overcome DOX the resistance in tumor cells thereby enhancing the effectiveness of DOX in OS, suggesting that YM155 in combination with DOX has potential in the treatment of osteosarcoma.
Keywords: Osteosarcoma; YM155; doxorubicin; survivn.