Masuda Akira, Maeno Ken, Nakagawa Taku, Saito Hiroko, Takahashi Takashi
Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanoko-den, Chikusa-ku, Nagoya 464-8681, Japan.
Am J Pathol. 2003 Sep;163(3):1109-16. doi: 10.1016/S0002-9440(10)63470-0.
Anti-microtubule agents such as vinorelbine and paclitaxel, which are extensively used in the treatment of lung cancers, activate mitotic spindle checkpoint. Although defects of the mitotic spindle checkpoint are thought to play a role in the genesis of chromosome instability, we previously reported its frequent impairment in human lung cancer cell lines. In this study, we examined a panel of 13 human cancer cell lines comprising 11 lung and 2 other cancers and found a significant difference in the resistance to apoptosis induced by anti-microtubule agents between mitotic spindle checkpoint-impaired and -proficient cancer cell lines. This finding was in marked contrast to a lack of such correlation with a DNA damaging agent, cis-platin. Interestingly, anti-microtubule agent-induced apoptosis in mitotic spindle checkpoint-proficient cell lines, NCI-H460 and A549, was shown to be markedly reduced by staurosporine treatment in association with the shortened mitotic arrest, whereas various inhibitors of caspases seemed to have very modest effects. Taken together, these findings suggest the potential involvement of mitotic spindle checkpoint in the induction of apoptosis by anti-microtubule agents in human lung cancers, warranting further studies on the underlying mechanisms.
抗微管药物如长春瑞滨和紫杉醇，被广泛用于肺癌治疗，它们会激活有丝分裂纺锤体检查点。尽管有丝分裂纺锤体检查点缺陷被认为在染色体不稳定性的发生中起作用，但我们之前报道过其在人肺癌细胞系中经常受损。在本研究中，我们检测了一组由11种肺癌和2种其他癌症组成的13种人类癌细胞系，发现有丝分裂纺锤体检查点受损和功能正常的癌细胞系对抗微管药物诱导的凋亡的抗性存在显著差异。这一发现与缺乏与DNA损伤剂顺铂的这种相关性形成了鲜明对比。有趣的是，在有丝分裂纺锤体检查点功能正常的细胞系NCI-H460和A549中，抗微管药物诱导的凋亡在与缩短的有丝分裂停滞相关的情况下，通过星形孢菌素处理显著减少，而各种半胱天冬酶抑制剂似乎作用甚微。综上所述，这些发现表明有丝分裂纺锤体检查点可能参与了抗微管药物在人肺癌中诱导凋亡的过程，这值得对其潜在机制进行进一步研究。
