Miltirone Is a Dual Inhibitor of P-Glycoprotein and Cell Growth in Doxorubicin-Resistant HepG2 Cells
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- 作者：Xuelin Zhou ; Yan Wang ; Wayne Y. W. Lee ; Penelope M. Y. Or ; David C. C. Wan ; Yiu Wa Kwan ; John H. K. Yeung
- 刊名：Journal of Natural Products
- 出版年：2015
- 出版时间：September 25, 2015
- 年：2015
- 卷：78
- 期：9
- 页码：2266-2275
- 全文大小：691K
- ISSN：1520-6025
文摘
Miltirone (1), an abietane-type diterpene quinone isolated from Salvia miltiorrhiza, possesses anticancer activity in p-glycoprotein (P-gp)-overexpressing human cancer cells. Results of the current study suggest a dual effect of miltirone on P-gp inhibition and apoptotic induction in a human hepatoma HepG2 cell line and its P-gp-overexpressing doxorubicin-resistant counterpart (R-HepG2). Miltirone (1) elicited a concentration-dependent cytotoxicity, with a similar potency (EC50 鈮?7鈥?2 渭M), in HepG2 and R-HepG2 cells. Miltirone (1) (1.56鈥?.25 渭M) produced synergistic effects on doxorubicin (DOX)-induced growth inhibition of R-HepG2 (synergism: 0.3 < combination index < 0.5). Molecular docking studies illustrated that miltirone (1) interacted with the active site of P-gp with a higher binding affinity than DOX, suggesting that it was a P-gp inhibitor. Flow cytometric analysis confirmed miltirone (1) as a competitive inhibitor of P-gp. At non-necrotic concentrations (1.56鈥?5 渭M), miltirone (1) activated caspase-dependent apoptotic pathways and triggered the generation of reactive oxygen species (ROS) and ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways (e.g., p38 MAPK, stress-activated protein kinase/c-Jun N-terminal kinase, and extracellular regulated kinase 1/2) in both HepG2 and R-HepG2 cells. Thus, we conclude that miltirone (1) is a dual inhibitor of P-gp and cell growth in human drug-resistant hepatoma cells.