Aerobic glycolysis is a hallmark of malignant tumor. Here, the hyperactive glycolysis in multidrug-resistant A549/Taxol cells was demonstrated to be essential for maintaining the vigorous cell viability and drug resistance. 5-(4-ethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-amine (YAN), a newly synthesized tubulin inhibitor, could not only inhibit the glycolysis in A549 and A549/Taxol cells through down-regulating the glycolysis-related proteins, but also disrupt the mitochondrial localization of hexokinase-2 (HK-2) which is related with the apoptosis resistance. The effects of YAN above were relevant to the down-regulation of PI3K-Akt-c-Myc/HIF-1α pathway. Moreover, YAN induced the reactive oxygen species generation in A549 and A549/Taxol cells, which only mediated the apoptosis in A549 cells. We also showed that 2-DG, the glycolysis inhibitor, synergistically enhanced YAN-triggered apoptosis in A549/Taxol cells via further suppressing glycolysis and reducing mitotic slippage. Collectively, we illustrate the inhibition effect of YAN on the glycolysis in A549 and A549/Taxol cells, and provide a fresh insight into the mechanism for the development of YAN as a candidate for multidrug resistant cancer treatment. The finding that 2-DG improved the anti-tumor efficacy of YAN against A549/Taxol cells, offers a reference for solving mitotic slippage-mediated drug resistance.

有氧糖酵解是恶性肿瘤的标志。在这里，耐多药 A549/紫杉醇细胞中的过度活跃的糖酵解被证明对于维持旺盛的细胞活力和耐药性是必不可少的。新合成的微管蛋白抑制剂5-(4-乙氧基苯基)-1-(3,4,5-三甲氧基苯基)-1H-1,2,4-三唑-3-胺(YAN)不仅能抑制糖酵解A549 和 A549/Taxol 细胞通过下调糖酵解相关蛋白，同时也破坏与凋亡抗性相关的 hexokinase-2 (HK-2) 的线粒体定位。上述YAN的作用与PI3K-Akt-c-Myc/HIF-1α通路的下调有关。此外，YAN 诱导 A549 和 A549/Taxol 细胞产生活性氧，仅介导 A549 细胞凋亡。我们还发现，糖酵解抑制剂 2-DG，通过进一步抑制糖酵解和减少有丝分裂滑动，协同增强 YAN 引发的 A549/紫杉醇细胞凋亡。总之，我们说明了 YAN 对 A549 和 A549/紫杉醇细胞糖酵解的抑制作用，并为 YAN 作为多药耐药癌症治疗候选者的发展机制提供了新的见解。发现2-DG提高了YAN对A549/Taxol细胞的抗肿瘤功效，为解决有丝分裂介导的耐药性提供了参考。并为 YAN 作为多药耐药癌症治疗候选者的发展机制提供了新的见解。发现2-DG提高了YAN对A549/Taxol细胞的抗肿瘤功效，为解决有丝分裂介导的耐药性提供了参考。并为 YAN 作为多药耐药癌症治疗候选者的发展机制提供了新的见解。发现2-DG提高了YAN对A549/Taxol细胞的抗肿瘤功效，为解决有丝分裂介导的耐药性提供了参考。