Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate.
Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate.
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DOI：
10.1158/1535-7163.mct-08-0684
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发表时间：
2008-11
影响因子：
5.7
通讯作者：
Mitchison TJ
中科院分区：
文献类型：
--
作者：
Orth JD;Tang Y;Shi J;Loy CT;Amendt C;Wilm C;Zenke FT;Mitchison TJ
驱动蛋白-5抑制剂（K5 Is）是有希望的抗有丝分裂癌症候选药物。它们导致癌细胞的长时间有丝分裂停滞和死亡，但它们在不同细胞类型中的全方位表型效应尚不清楚。使用癌症和正常细胞系的延时显微镜，我们发现一种新的K5 I导致几种不同的癌症和非癌细胞类型在单极有丝分裂中经历长时间的停滞。然而，随后的事件在细胞类型之间差异很大。正常的二倍体细胞大多数从有丝分裂中滑落并停滞在四倍体G1中，几乎没有细胞死亡。一些癌细胞系在有丝分裂停滞期间死亡，或在滑动之后死亡。与流行的观点相反，有丝分裂滑移不是死亡所必需的，并且在大多数细胞系中，有丝分裂停滞的持续时间与死亡的概率相关性很差。我们还分析了药物的可逆性，以及MCF 7乳腺癌细胞短暂药物暴露后的长期反应。虽然许多细胞在有丝分裂期间药物洗脱后分裂，但与自发滑移后洗脱相比，该处理导致存活率较低，可能是由于分裂细胞中的染色体分离错误。我们的分析表明，K5 Is导致癌症选择性细胞杀伤，为理解临床反应提供了重要的动力学信息，并阐明了表型水平上药物敏感性与耐药性的机制。
Kinesin-5 inhibitors (K5Is) are promising anti-mitotic cancer drug candidates. They cause prolonged mitotic arrest and death of cancer cells, but their full range of phenotypic effects in different cell types has been unclear. Using time-lapse microscopy of cancer and normal cell lines, we find that a novel K5I causes several different cancer and non-cancer cell types to undergo prolonged arrest in monopolar mitosis. Subsequent events, however, differed greatly between cell types. Normal diploid cells mostly slipped from mitosis and arrested in tetraploid G1, with little cell death. Several cancer cell lines either died during mitotic arrest, or following slippage. Contrary to prevailing views, mitotic slippage was not required for death, and the duration of mitotic arrest correlated poorly with the probability of death in most cell lines. We also assayed drug reversibility, and long-term responses after transient drug exposure in MCF7 breast cancer cells. While many cells divided after drug washout during mitosis, this treatment resulted in lower survival compared to washout after spontaneous slippage, likely due to chromosome segregation errors in the cells that divided. Our analysis shows that K5Is cause cancer-selective cell killing, provides important kinetic information for understanding clinical responses, and elucidates mechanisms of drug sensitivity versus resistance at the level of phenotype.