Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells.
Mdivi-1 induces spindle abnormalities and augments taxol cytotoxicity in MDA-MB-231 cells.
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DOI：
10.1038/s41420-021-00495-z
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发表时间：
2021-05-20
影响因子：
7
通讯作者：
Yih LH
中科院分区：
文献类型：
--
作者：
Fang CT;Kuo HH;Yuan CJ;Yao JS;Yih LH
紫杉醇是多种癌症的一线化疗药物，包括高度难治性三阴性乳腺癌 (TNBC)。然而，它往往与乳腺癌患者的毒副作用和化疗耐药有关，这极大地限制了该药物的临床应用。因此，与紫杉醇协同作用以促进细胞毒性的化合物可能有助于提高基于紫杉醇的化疗的功效。在这项研究中，我们证明 mdivi-1（一种假定的线粒体裂变蛋白 Drp1 抑制剂）可增强紫杉醇的抗癌作用并克服 TNBC 细胞系 (MDA-MB-231) 中的紫杉醇耐药性。 mdivi-1 不仅在单独使用时诱导有丝分裂纺锤体异常和有丝分裂停滞，而且在联合使用时还增强了紫杉醇诱导的抗有丝分裂作用。此外，mdivi-1 在紫杉醇抗性细胞系中诱导显着的纺锤体异常和细胞毒性，表明它可以克服紫杉醇抗性。值得注意的是，mdivi-1 的抗有丝分裂作用并不伴随线粒体的显着形态或功能改变，并且不依赖于 Drp1。相反，mdivi-1 在 μM 水平上表现出对微管蛋白的亲和力，抑制微管蛋白聚合，并在细胞进入有丝分裂时立即破坏纺锤体组装。总之，我们的结果表明，mdivi-1 与微管蛋白结合并阻碍微管蛋白聚合，这种作用可能是其抗有丝分裂活性及其增强紫杉醇细胞毒性和克服 MDA-MB-231 细胞中紫杉醇耐药性的能力的基础。此外，我们的数据表明 mdivi-1 可能有助于提高紫杉醇对乳腺癌的治疗效果。
Taxol is a first-line chemotherapeutic for numerous cancers, including the highly refractory triple-negative breast cancer (TNBC). However, it is often associated with toxic side effects and chemoresistance in breast cancer patients, which greatly limits the clinical utility of the drug. Hence, compounds that act in concert with taxol to promote cytotoxicity may be useful to improve the efficacy of taxol-based chemotherapy. In this study, we demonstrated that mdivi-1, a putative inhibitor of mitochondrial fission protein Drp1, enhances the anticancer effects of taxol and overcomes taxol resistance in a TNBC cell line (MDA-MB-231). Not only did mdivi-1 induce mitotic spindle abnormalities and mitotic arrest when used alone, but it also enhanced taxol-induced antimitotic effects when applied in combination. In addition, mdivi-1 induced pronounced spindle abnormalities and cytotoxicity in a taxol-resistant cell line, indicating that it can overcome taxol resistance. Notably, the antimitotic effects of mdivi-1 were not accompanied by prominent morphological or functional alterations in mitochondria and were Drp1-independent. Instead, mdivi-1 exhibited affinity to tubulin at μM level, inhibited tubulin polymerization, and immediately disrupted spindle assembly when cells entered mitosis. Together, our results show that mdivi-1 associates with tubulin and impedes tubulin polymerization, actions which may underlie its antimitotic activity and its ability to enhance taxol cytotoxicity and overcome taxol resistance in MDA-MB-231 cells. Furthermore, our data imply a possibility that mdivi-1 could be useful to improve the therapeutic efficacy of taxol in breast cancer.
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影响因子：
5.2
作者：
Akita, Mamoru;Suzuki-Karasaki, Miki;Suzuki-Karasaki, Yoshihiro
通讯作者：
Suzuki-Karasaki, Yoshihiro
影响因子：
8
作者：
Fang, Chieh-Ting;Kuo, Hsiao-Hui;Yih, Ling-Huei
通讯作者：
Yih, Ling-Huei
影响因子：
3.7
作者：
Lugli, E;Troiano, L;Cossarizza, A
通讯作者：
Cossarizza, A
DOI：
10.1073/pnas.191388598
发表时间：
2001-09-25
影响因子：
11.1
作者：
Gonçalves, A;Braguer, D;Jordan, MA
通讯作者：
Jordan, MA
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi