A novel taxane, difluorovinyl-ortataxel, effectively overcomes paclitaxel-resistance in breast cancer cells
A novel taxane, difluorovinyl-ortataxel, effectively overcomes paclitaxel-resistance in breast cancer cells
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一种新型紫杉烷二氟乙烯基-ortataxel可有效克服乳腺癌细胞对紫杉醇的耐药性
DOI：
10.1016/j.canlet.2020.06.025
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发表时间：
2020-10-28
期刊：
影响因子：
9.7
通讯作者：
Wang, Haihe
中科院分区：
文献类型：
--
作者：
Rong, Dade;Wang, Changwei;Wang, Haihe
紫杉醇（PTX）广泛用于治疗乳腺癌和卵巢癌，但先天性和获得性耐药性常常影响其应用。本研究的目的是筛选新一代紫杉烷类药物，以检测其对紫杉醇敏感和耐药的乳腺癌细胞的有效性。在12种化合物中，二氟乙烯基奥他赛（DFV - OTX）对紫杉醇敏感和耐药的乳腺癌细胞均显示出强大的细胞毒活性。此外，DFV - OTX有效诱导微管蛋白/微管聚合以及G2/M期阻滞，导致紫杉醇敏感和耐药的癌细胞发生凋亡。分子对接分析表明，DFV - OTX与β - 微管蛋白具有独特的氢键和范德华相互作用。液相色谱 - 串联质谱（LC - MS/MS）分析还表明，DFV - OTX的细胞内药物含量低于PTX，这对于克服紫杉醇耐药性至关重要。此外，DFV - OTX在小鼠模型的MCF - 7R和MDA - MB - 231R肿瘤异种移植物中表现出明显的疗效。综上所述，我们的研究结果表明，新型紫杉烷DFV - OTX能够有效克服MDA - MB - 231R细胞中的紫杉醇耐药性，其中耐药性归因于ABCB1/ABCG2的上调；并且在MCF - 7R细胞中具有独特的作用模式。我们的研究结果有力地表明，DFV - OTX是一种有前途的用于治疗紫杉醇耐药癌症的化疗药物。
Paclitaxel (PTX) is widely used to treat breast and ovarian cancers, but innate and acquired resistance often compromises its applications. The objective of this study was to screen new-generation taxanes for their efficiency against both PTX-sensitive and PTX-resistant breast cancer cells. From twelve compounds, difluorovinylortataxel (DFV-OTX) displayed potent cytotoxic activities against both PTX-sensitive and PTX-resistant breast cancer cells. Moreover, DFV-OTX effectively induced tubulin/microtubule polymerization and G2/M phase arrest, leading to apoptosis in both PTX-sensitive and PTX-resistant cancer cells. Molecular docking analysis showed that DFV-OTX possesses unique hydrogen-bonding and van der Waals interactions with beta-tubulin. LC-MS/MS analysis also demonstrated that the intracellular drug amount of DFV-OTX was lower than that of PTX, which would be critical to overcome PTX-resistance. Furthermore, DFV-OTX exhibited clear efficacy in the MCF-7R and MDA-MB-231R tumor xenografts in mouse models. Taken together, our results demonstrate that the novel taxane, DFV-OTX, can effectively overcome PTX-resistance in MDA-MB-231R cells, wherein the drug resistance was attributed to ABCB1/ABCG2 upregulation and a distinct mode of action in MCF-7R cells. Our results strongly indicate that DFV-OTX is a promising chemotherapeutic agent for the treatment of PTX-resistant cancers.