Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, China.
Biochem Pharmacol. 2011 Dec 1;82(11):1593-603. doi: 10.1016/j.bcp.2011.08.012. Epub 2011 Aug 17.
Currently, multi-drug resistance (MDR) to anticancer drugs is a major obstacle to successful treatment of cancer. Looking for novel compounds with anti-MDR activity is an effectively way to overcome cancer drug resistance. Here, we found that H1, a novel derivate of Tetrandrine, displayed anti-MDR activity in vitro and in vivo. Average resistant factor of H1 is only 1.6. In KB and KBv200 cancer cells xenograft mice, H1 also displayed favorable anti-MDR activity. It could induce typical apoptosis as indicated by morphologic changes, DNA fragmentation in sensitive and resistant cancer cells. Further studies showed that H1 treatment resulted in the increase of ROS generation, elevation of the Bax/Bcl-2 ratio, loss of mitochondrial transmembrane potential (ΔΨ(m)), release of cytochrome c and AIF from mitochondria into cytosol, and activation of caspase-9 and caspase-3, but had no effect on activation of caspase-8 and the expression of Fas/FasL. On the other hand, H1 also inhibited survival pathways such as the activation of Erk1/2 and Akt1/2. In conclusion, H1 exerts good anti-MDR activity in vitro and in vivo, its mechanisms may be associated with initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2. These findings further support the potential of H1 to be used in clinical trial of MDR cancer treatment.
目前，多药耐药（MDR）是癌症治疗成功的主要障碍。寻找具有抗 MDR 活性的新型化合物是克服癌症药物耐药性的有效方法。在这里，我们发现 H1，一种新的汉防己甲素衍生物，在体外和体内均显示出抗 MDR 活性。H1 的平均耐药因子仅为 1.6。在 KB 和 KBv200 癌细胞异种移植小鼠中，H1 也表现出良好的抗 MDR 活性。它可以诱导敏感和耐药癌细胞形态变化、DNA 片段化的典型凋亡。进一步的研究表明，H1 处理导致 ROS 生成增加，Bax/Bcl-2 比值升高，线粒体跨膜电位（ΔΨ（m））丧失，细胞色素 c 和 AIF 从线粒体释放到细胞质中，以及 caspase-9 和 caspase-3 的激活，但对 caspase-8 的激活和 Fas/FasL 的表达没有影响。另一方面，H1 还抑制了生存途径，如 Erk1/2 和 Akt1/2 的激活。总之，H1 在体外和体内均显示出良好的抗 MDR 活性，其机制可能与启动内在凋亡途径和抑制 Erk1/2 和 Akt1/2 的激活有关。这些发现进一步支持了 H1 用于 MDR 癌症治疗临床试验的潜力。
