Background Drugs such as taxanes, epothilones, and vinca alkaloids are widely used in the treatment of breast, ovarian, and lung cancers but come with major side effects such as neuropathy and loss of neutrophils and as single agents have a lack of efficacy. M2I-1 (MAD2 inhibitor-1) has been shown to disrupt the CDC20-MAD2 interaction, and consequently, the assembly of the mitotic checkpoint complex (MCC). Results We report here that M2I-1 can significantly increase the sensitivity of several cancer cell lines to anti-mitotic drugs, with cell death occurring after a prolonged mitotic arrest. In the presence of nocodazole or taxol combined with M2I-1 cell death is triggered by the premature degradation of Cyclin B1, the perturbation of the microtubule network, and an increase in the level of the pro-apoptotic protein MCL-1s combined with a marginal increase in the level of NOXA. The elevated level of MCL-1s and the marginally increased NOXA antagonized the increased level of MCL-1, a pro-survival protein of the Bcl-2 family. Conclusion Our results provide some important molecular mechanisms for understanding the relationship between the mitotic checkpoint and programmed cell death and demonstrate that M2I-1 exhibits antitumor activity in the presence of current anti-mitotic drugs such as taxol and nocodazole and has the potential to be developed as an anticancer agent.

中文翻译：

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M2I-1 破坏 CDC20 和 MAD2 之间的体内相互作用，并通过 MCL-1 增加癌细胞系对抗有丝分裂药物的敏感性。

背景 紫杉烷类、埃坡霉素和长春花生物碱等药物广泛用于治疗乳腺癌、卵巢癌和肺癌，但具有严重的副作用，如神经病变和中性粒细胞丢失，并且作为单一药物缺乏疗效。M2I-1 (MAD2 inhibitor-1) 已被证明可破坏 CDC20-MAD2 相互作用，从而破坏有丝分裂检查点复合物 (MCC) 的组装。结果 我们在此报告，M2I-1 可以显着增加几种癌细胞系对抗有丝分裂药物的敏感性，细胞死亡发生在长时间的有丝分裂停滞后。在诺考达唑或紫杉醇与 M2I-1 相结合的情况下，细胞死亡由 Cyclin B1 的过早降解、微管网络的扰动引发，促凋亡蛋白 MCL-1s 水平的增加与 NOXA 水平的边际增加相结合。MCL-1s 水平升高和 NOXA 略微增加可拮抗 Bcl-2 家族的促生存蛋白 MCL-1 水平升高。结作为抗癌剂。