Kawano Takeshi, Agata Naoki, Kharbanda Surender, Avigan David, Kufe Donald
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115 USA.
Cancer Chemother Pharmacol. 2007 Feb;59(3):329-35. doi: 10.1007/s00280-006-0274-x. Epub 2006 Jul 8.
The isocoumarin NM-3 reverses resistance of human multiple myeloma (MM) cells to dexamethasone and is in clinical trials. In the present work, the NM-3 analog, 185322, has been studied for activity against MM cells.
Human U266, RPMI8226 and primary MM cells were analyzed for the effects of 185322 on cell cycle distribution, tubulin polymerization and induction of apoptosis.
We show that, in contrast to NM-3, treatment with 185322 is associated with a marked arrest of MM cells in M phase. The results also demonstrate that treatment with 185322 is associated with a rapid decrease in tubulin assembly and an increase in Bcl-2 phosphorylation, consistent with disruption of mitosis. Our results further demonstrate that mitotic failure induced by 185322 results in activation of an apoptotic response in MM cell lines and primary MM cells. By contrast, 185322 had little if any effect on growth and survival of human carcinoma cells.
These findings identify a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of MM cells.
异香豆素NM - 3可逆转人多发性骨髓瘤（MM）细胞对地塞米松的耐药性，目前正处于临床试验阶段。在本研究中，对NM - 3类似物185322抗MM细胞的活性进行了研究。
分析了185322对人U266、RPMI8226细胞以及原代MM细胞的细胞周期分布、微管蛋白聚合和凋亡诱导的影响。
我们发现，与NM - 3不同，用185322处理会使MM细胞在M期显著停滞。结果还表明，用185322处理会导致微管蛋白组装迅速减少以及Bcl - 2磷酸化增加，这与有丝分裂的破坏一致。我们的结果进一步证明，185322诱导的有丝分裂失败会导致MM细胞系和原代MM细胞中凋亡反应的激活。相比之下，185322对人癌细胞的生长和存活几乎没有影响。
这些发现确定了一种新型的微管组装抑制剂，其可诱导MM细胞的有丝分裂停滞和凋亡。
