Abstract
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.
Highlights
Osteosarcoma (OS) is the most common malignant bone tumor that affects children and young adults [1]
The current standard treatment consists of combined chemotherapy with high doses of cisplatin, doxorubicin, and methotrexate, followed by surgical ablation and subsequent rounds of neoadjuvant chemotherapy
MX significantly inhibited growth in both osteosarcoma cell lines when compared to control at all concentrations and times tested (p < 0.05) (Figure 1(a)), though growth abrogation was neither time- nor concentration-dependent
Summary
Osteosarcoma (OS) is the most common malignant bone tumor that affects children and young adults [1]. The current standard treatment consists of combined chemotherapy with high doses of cisplatin, doxorubicin, and methotrexate, followed by surgical ablation and subsequent rounds of neoadjuvant chemotherapy. Radiotherapy, on the other hand, is indicated only in patients who suffer from inoperable tumors, painful bone metastases or those who refuse surgery. OS treatment outcome is often hampered by the tumor’s properties of metastasis and subsequent recurrence, with lung metastases as the major cause of death in these patients [2]. There is still a relentless pursuit for novel chemotherapeutic agents to prevent osteosarcoma disease progression, improve efficacy and to attenuate toxicity
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