Liu Min, Yu Haiyang, Huo Lihong, Liu Jianchao, Li Minggang, Zhou Jun
Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Biochem Pharmacol. 2008 Jul 15;76(2):169-78. doi: 10.1016/j.bcp.2008.04.018. Epub 2008 May 4.
Pancreatic cancer is a devastating disease with a high mortality rate. Treatment of this malignancy remains a big challenge in oncology, and none of the currently available chemotherapeutic agents has a remarkable impact on improving patient survival. Consequently, it is important to explore new targets and find effective drugs for the management of this disease. Here we report that inhibition of the mitotic kinesin Eg5 by a pharmacological compound effectively prevents the proliferation of pancreatic cancer cells by halting mitotic progression, resulting in robust apoptosis. The mitotic arrest induced by this agent is attributed to its interference with spindle formation and activation of the spindle checkpoint. Impairment of the spindle checkpoint significantly compromises both mitotic arrest and apoptosis induced by the Eg5 inhibitor, suggesting the importance of the spindle checkpoint in monitoring Eg5 inhibitor sensitivity. Furthermore, treatment of nude mice bearing tumor xenografts of human pancreatic cancer results in pronounced tumor regression by triggering apoptosis. These data thus indicate Eg5 as a potential target for pancreatic cancer treatment.
胰腺癌是一种死亡率很高的毁灭性疾病。这种恶性肿瘤的治疗仍然是肿瘤学中的一大挑战，目前可用的化疗药物中没有一种对提高患者生存率有显著影响。因此，探索新的靶点并找到治疗这种疾病的有效药物很重要。在此我们报告，一种药理化合物对有丝分裂驱动蛋白Eg5的抑制作用通过阻止有丝分裂进程有效地防止了胰腺癌细胞的增殖，从而导致强烈的细胞凋亡。该药物诱导的有丝分裂停滞归因于其对纺锤体形成的干扰和纺锤体检查点的激活。纺锤体检查点的受损显著损害了由Eg5抑制剂诱导的有丝分裂停滞和细胞凋亡，表明纺锤体检查点在监测Eg5抑制剂敏感性方面具有重要性。此外，对携带人胰腺癌肿瘤异种移植的裸鼠进行治疗，通过触发细胞凋亡导致肿瘤明显消退。因此，这些数据表明Eg5是胰腺癌治疗的一个潜在靶点。
