Wang Shengpeng, Wang Lu, Chen Meiwan, Wang Yitao
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China.
Chem Biol Interact. 2015 Jun 25;235:76-84. doi: 10.1016/j.cbi.2015.03.017. Epub 2015 Mar 27.
The development of resistance to chemotherapeutic agents remains a major challenge to breast cancer chemotherapy. Overexpression of drug efflux transporters like P-glycoprotein (P-gp) and resistance to apoptosis are the two key factors that confer cancer drug resistance. Gambogic acid (GA), a major component of Gamboge resin, has potent anticancer effects and can inhibit the growth of several types of human cancers. However, the potential and underlying mechanisms of GA in reversing cancer resistance remain poorly understood. In the present study, we found that GA can markedly sensitize doxorubicin (DOX)-resistant breast cancer cells to DOX-mediated cell death. GA increased the intracellular accumulation of DOX by inhibiting both P-gp expression and activity. Meanwhile, the combination effect was associated with the generation of intracellular reactive oxygen species (ROS) and the suppression of anti-apoptotic protein survivin. Scavenging intracellular ROS or overexpression of survivin blocked the sensitizing effects of GA in DOX-induced apoptosis. Furthermore, ROS-mediated activation of p38 MAPK was revealed in GA-mediated suppression of survivin expression. This study gives rise to the possibility of applying GA as an anticancer agent for the purpose of combating DOX-resistant breast cancer.
对化疗药物产生耐药性仍然是乳腺癌化疗面临的一项重大挑战。像P-糖蛋白（P-gp）这样的药物外排转运蛋白的过表达以及对凋亡的抗性是导致癌症耐药的两个关键因素。藤黄酸（GA）是藤黄树脂的主要成分，具有强大的抗癌作用，能够抑制多种人类癌症的生长。然而，GA在逆转癌症耐药性方面的潜力和潜在机制仍知之甚少。在本研究中，我们发现GA能显著使多柔比星（DOX）耐药的乳腺癌细胞对DOX介导的细胞死亡敏感。GA通过抑制P-gp的表达和活性增加了DOX在细胞内的蓄积。同时，联合效应与细胞内活性氧（ROS）的产生以及抗凋亡蛋白生存素的抑制有关。清除细胞内ROS或生存素过表达可阻断GA在DOX诱导的凋亡中的增敏作用。此外，在GA介导的生存素表达抑制中发现了ROS介导的p38丝裂原活化蛋白激酶（MAPK）的激活。本研究为将GA作为一种抗癌药物用于对抗DOX耐药的乳腺癌提供了可能性。
