Miltirone Is a Dual Inhibitor of P-Glycoprotein and Cell Growth in Doxorubicin-Resistant HepG2 Cells
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摘要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 approximate to 7-12 mu M), in HepG2 and R-HepG2 cells. Miltirone (1) (1.56-6.25 mu 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 (1.56-25 mu 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.
著者Zhou XL, Wang Y, Lee WYW, Or PMY, Wan DCC, Kwan YW, Yeung JHK
期刊名稱Journal of Natural Products
出版年份2015
月份9
日期1
卷號78
期次9
出版社AMER CHEMICAL SOC
頁次2266 - 2275
國際標準期刊號0163-3864
電子國際標準期刊號1520-6025
語言英式英語
Web of Science 學科類別Chemistry, Medicinal; Pharmacology & Pharmacy; Plant Sciences

上次更新時間 2020-21-09 於 01:22