Department of Oral and Maxillofacial Surgery, College of Stomatology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Basic Clin Pharmacol Toxicol. 2013 Jan;112(1):25-33. doi: 10.1111/j.1742-7843.2012.00921.x. Epub 2012 Aug 22.
Gambogic acid (GA) is known for its anti-cancer activity in a phase II clinical trial. However, the detailed molecular mechanisms of its anti-multidrug resistance remain unclear. The present study was designed to study the relationship between GA and multidrug-resistant protein ATP-binding cassette transporter B1 (ABCB1). GA dose dependently inhibited ABCB1 activity levels in the in vitro Pgp-Glo assay system and increased the cellular accumulation of ABCB1 substrate adriamycin. Although GA had no significant influence on ABCB1 mRNA in the real-time PCR assay, Western blot detection indicated the compound reduced ABCB1 protein levels. Further study showed the proteasome inhibitor MG-132 reversed the GA-decreased ABCB1 level and prolonged half-life of ABCB1. It was also found that GA coordinated with other anti-cancer drugs (such as adriamycin, docetaxel, verapamil and protopanaxadiol) to enhance cellular cytotoxicity on human epithelial cancer cell lines with higher ABCB1 expression levels. These data suggest that GA functions as a non-competitive inhibitor of ABCB1 by directly inhibiting and reducing its expression levels by promoting protein degradation through post-translational proteasome pathway. The results of this study will aid in the understanding of the synergistic effects of combining GA with other drugs as a new anti-multidrug-resistant agent.
藤黄酸（GA）在 II 期临床试验中因其抗癌活性而闻名。然而，其抗多药耐药的详细分子机制尚不清楚。本研究旨在研究 GA 与多药耐药蛋白三磷酸腺苷结合盒转运体 B1（ABCB1）之间的关系。GA 呈剂量依赖性抑制体外 Pgp-Glo 测定系统中的 ABCB1 活性水平，并增加 ABCB1 底物阿霉素的细胞内积累。虽然 GA 在实时 PCR 测定中对 ABCB1 mRNA 没有显著影响，但 Western blot 检测表明该化合物降低了 ABCB1 蛋白水平。进一步的研究表明蛋白酶体抑制剂 MG-132 逆转了 GA 降低的 ABCB1 水平并延长了 ABCB1 的半衰期。还发现 GA 与其他抗癌药物（如阿霉素、多西他赛、维拉帕米和原人参二醇）协同作用，增强了 ABCB1 表达水平较高的人上皮癌细胞系的细胞毒性。这些数据表明，GA 通过直接抑制和降低其表达水平，通过翻译后蛋白酶体途径促进蛋白降解，作为 ABCB1 的非竞争性抑制剂发挥作用。本研究的结果将有助于理解将 GA 与其他药物联合作为一种新的抗多药耐药药物的协同作用。
