Abstract
Lung metastasis markedly reduces the prognosis of osteosarcoma. Moreover, there is no effective treatment for lung metastasis, and a new treatment strategy for the treatment of osteosarcoma lung metastasis is required. Therefore, in this study, we investigated the suppressive effect of the microtubule inhibitor eribulin mesylate (eribulin) on lung metastasis of osteosarcoma. At concentrations >proliferation IC50, eribulin induced cell cycle arrest and apoptosis in a metastatic osteosarcoma cell line, LM8. However, at concentrations <proliferation IC50, (low dose), eribulin changed cell morphology and decreased LM8 migration. Low eribulin concentrations also reduced directionality during migration, peripheral localization of adenomatous polyposis coli protein, and turnover of focal adhesions. In a three-dimensional collagen culture system, low eribulin concentrations inhibited tumor cell proliferation and colony formation. Higher doses of eribulin administered on a standard schedule inhibited lung metastasis and primary tumor growth in a murine osteosarcoma metastasis model. Frequent low-dose eribulin administration (0.3 mg/kg every 4 days × 4) effectively inhibited lung metastasis but had little effect on primary tumor growth. Overall, our results indicate that eribulin could reduce osteosarcoma lung metastasis.
Highlights
Osteosarcoma is the most common malignant bone tumor among children and adolescents
We first investigated whether eribulin inhibits osteosarcoma lung metastasis in a mouse model using a clinical administration schedule
The colony number significantly decreased in the treatment group (Figure 1G) relative to that in the control group. These results indicate that eribulin reduced primary tumor growth and lung metastasis of osteosarcoma
Summary
Osteosarcoma is the most common malignant bone tumor among children and adolescents. The prognosis of osteosarcoma has been poor over the past thirty years. The overall five-year survival rates without and with metastasis at the time of diagnosis are 60–70% and 15– 20%, respectively [1, 2] mainly because there are few therapeutic options for lung metastasis of osteosarcoma. The most effective treatment option so far is neoadjuvant chemotherapy developed in the 1980s and consisting of high-dose methotrexate, doxorubicin, and cisplatin (MAP) [3, 4]. No clinical trials for metastasis inhibition have improved the outcome of patients with osteosarcoma, especially for those who respond poorly to MAP regimens [5, 6]. A new treatment strategy for osteosarcoma lung metastasis is required
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