Centre for Translational Medicine, The First Affiliated Hospital, SUN Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China; Department of Biochemistry, Zhongshan School of Medicine, SUN Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China.
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, 11794-3400, USA.
Cancer Lett. 2020 Oct 28;491:36-49. doi: 10.1016/j.canlet.2020.06.025. Epub 2020 Jul 27.
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, difluorovinyl-ortataxel (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 β-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.
紫杉醇（PTX）被广泛用于治疗乳腺癌和卵巢癌，但内源性和获得性耐药经常影响其应用。本研究的目的是筛选新一代紫杉烷类药物对紫杉醇敏感和耐药的乳腺癌细胞的疗效。在 12 种化合物中，二氟乙烯基奥他他醇（DFV-OTX）对紫杉醇敏感和耐药的乳腺癌细胞均表现出强大的细胞毒性作用。此外，DFV-OTX 能有效诱导微管蛋白/微管聚合和 G2/M 期阻滞，导致紫杉醇敏感和耐药癌细胞凋亡。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。LC-MS/MS 分析还表明，DFV-OTX 的细胞内药物量低于 PTX，这对于克服 PTX 耐药性至关重要。此外，DFV-OTX 在 MCF-7R 和 MDA-MB-231R 肿瘤异种移植小鼠模型中表现出明显的疗效。综上所述，我们的研究结果表明，新型紫杉烷类药物 DFV-OTX 可以有效地克服 MDA-MB-231R 细胞中的 PTX 耐药性，其中耐药性归因于 ABCB1/ABCG2 的上调和 MCF-7R 细胞中独特的作用模式。我们的研究结果强烈表明，DFV-OTX 是一种有前途的治疗 PTX 耐药性癌症的化疗药物。
