Watanabe Kenta, Yui Yoshihiro, Sasagawa Satoru, Suzuki Kayo, Kanamori Masahiko, Yasuda Taketoshi, Kimura Tomoatsu
Department of Orthopedic Surgery, University of Toyama, Toyama, Japan.
Research Institute, Nozaki Tokushukai Hospital, Osaka, Japan.
Oncotarget. 2019 Jan 4;10(2):161-174. doi: 10.18632/oncotarget.26536.
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 IC, eribulin induced cell cycle arrest and apoptosis in a metastatic osteosarcoma cell line, LM8. However, at concentrations <proliferation IC, (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.
肺转移显著降低骨肉瘤的预后。此外，对于肺转移尚无有效的治疗方法，因此需要一种新的治疗骨肉瘤肺转移的策略。所以，在本研究中，我们探究了微管抑制剂甲磺酸艾瑞布林（艾瑞布林）对骨肉瘤肺转移的抑制作用。在浓度高于增殖IC时，艾瑞布林可诱导转移性骨肉瘤细胞系LM8的细胞周期停滞和凋亡。然而，在浓度低于增殖IC（低剂量）时，艾瑞布林改变细胞形态并降低LM8的迁移能力。低浓度的艾瑞布林还会降低迁移过程中的方向性、腺瘤性息肉病大肠杆菌蛋白的外周定位以及粘着斑的周转。在三维胶原培养系统中，低浓度的艾瑞布林可抑制肿瘤细胞增殖和集落形成。在小鼠骨肉瘤转移模型中，按照标准方案给予较高剂量的艾瑞布林可抑制肺转移和原发肿瘤生长。频繁给予低剂量艾瑞布林（每4天0.3 mg/kg，共4次）可有效抑制肺转移，但对原发肿瘤生长影响较小。总体而言，我们的结果表明艾瑞布林可减少骨肉瘤的肺转移。
