Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Anticancer Drugs. 2011 Nov;22(10):995-1001. doi: 10.1097/CAD.0b013e32834a16d4.
Osteosarcoma is the most common primary malignant tumor of bone, which frequently occurs in the second decade of life. Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with chemoresistant or metastatic tumors is still poor. Therefore, there is a need for the development of more efficient therapeutic agents. BI 2536, an innovative selective inhibitor of Polo-like kinase 1, has shown anticancer potential promoting mitotic arrest and apoptosis in a variety of tumor cells, including osteosarcoma. Here, we present more evidence of the antiproliferative effects of BI 2536 on HOS and MG-63 osteosarcoma cell lines. Our results showed that nanomolar concentrations (10, 50, and 100 nmol/l) of the drug significantly decreased cell proliferation and clonogenic capacity, inducing mitotic arrest and aneuploidy. Interestingly, although BI 2536 mediated a moderate increase of apoptosis after 48 h in HOS cells, no increased caspase-3 activity was detected for MG-63 cells. In contrast to previous studies, we show that perturbation of normal mitotic progression by BI 2536 in these osteosarcoma cell lines results in caspase-independent mitotic catastrophe followed by necrosis. Our findings reinforce the likelihood of directing against Polo-like kinase 1 as a therapeutic option in the treatment of osteosarcoma.
骨肉瘤是最常见的原发性骨恶性肿瘤，常发生在人生的第二个十年。尽管新辅助化疗有所改善，但对化疗耐药或转移性肿瘤患者的治疗效果仍然较差。因此，需要开发更有效的治疗药物。BI 2536 是一种新型的 Polo 样激酶 1 选择性抑制剂，在多种肿瘤细胞中，包括骨肉瘤中，显示出促进有丝分裂停滞和细胞凋亡的抗癌潜力。在这里，我们提供了更多证据表明 BI 2536 对 HOS 和 MG-63 骨肉瘤细胞系具有抗增殖作用。我们的结果表明，该药物的纳摩尔浓度（10、50 和 100 nmol/l）显著降低了细胞增殖和集落形成能力，诱导有丝分裂停滞和非整倍体。有趣的是，尽管 BI 2536 在 HOS 细胞中 48 小时后介导了适度增加的细胞凋亡，但未检测到 MG-63 细胞中 caspase-3 活性的增加。与之前的研究不同，我们表明 BI 2536 在这些骨肉瘤细胞系中对正常有丝分裂进程的干扰导致细胞凋亡-independent 有丝分裂灾难，随后发生坏死。我们的研究结果加强了将 Polo 样激酶 1 作为骨肉瘤治疗的一种治疗选择的可能性。
