State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
Aging (Albany NY). 2020 Feb 28;12(4):3713-3729. doi: 10.18632/aging.102842.
P-glycoprotein (P-gp) and βIII-tubulin overexpression-mediated drug resistance leads to clinical therapy failure for paclitaxel. However, the development of paclitaxel-resistance reversal agents has not had much success. In this study, EM-E-11-4, a lathyrane-type diterpenoid extracted from , demonstrated good anti-MDR (multidrug resistance) activity in paclitaxel-resistant tumor cells overexpressing either P-gp or βIII-tubulin. EM-E-11-4 was able to recover the effects of paclitaxel in inducing arrest at G/M phase and apoptosis in both A549/Tax (P-gp overexpression) and Hela/βIII (βIII-tubulin overexpression) cells, respectively, at a non-cytotoxic dose. EM-E-11-4 could enable Flutax-1 and Rhodamine 123 be accumulated intracellularly at an accelerating rate in A549/Tax cells by inhibiting the activity of P-gp ATPase, rather than affecting the expression of P-gp. In addition, it also strengthened the effects of paclitaxel in promoting tubulin polymerization and the binding of paclitaxel to microtubules It inhibited the expression of βIII-tubulin in Hela/βIII cells in a dose-dependent manner while not exerting influence on the other β-tubulin subtypes. As far as we know, this is the first study to report that a small molecule natural product could specifically inhibit the expression of βIII-tubulin. These results suggest EM-E-11-4 may serve as a promising MDR reversal agent, particularly for patients bearing tumors with high expression of P-gp and βIII-tubulin.
P-糖蛋白（P-gp）和βIII-微管蛋白过表达介导的药物耐药性导致紫杉醇临床治疗失败。然而，紫杉醇耐药逆转剂的开发并没有取得太大成功。在这项研究中，从 中提取的拉坦型二萜 EM-E-11-4 对表达 P-gp 或 βIII-微管蛋白的紫杉醇耐药肿瘤细胞表现出良好的抗多药耐药（MDR）活性。在非细胞毒性剂量下，EM-E-11-4 能够恢复紫杉醇诱导 A549/Tax（P-gp 过表达）和 Hela/βIII（βIII-微管蛋白过表达）细胞分别在 G/M 期停滞和凋亡的作用。EM-E-11-4 通过抑制 P-gp ATP 酶的活性，能够加速 Flutax-1 和 Rhodamine 123 在 A549/Tax 细胞内的积累，而不影响 P-gp 的表达。此外，它还增强了紫杉醇促进微管蛋白聚合和紫杉醇与微管结合的作用。它以剂量依赖的方式抑制 Hela/βIII 细胞中βIII-微管蛋白的表达，而对其他β-微管蛋白亚型没有影响。据我们所知，这是第一项报道小分子天然产物能够特异性抑制βIII-微管蛋白表达的研究。这些结果表明，EM-E-11-4 可能是一种有前途的多药耐药逆转剂，特别是对表达 P-gp 和βIII-微管蛋白较高的肿瘤患者。
