Miltirone Is a Dual Inhibitor of P-Glycoprotein and Cell Growth in Doxorubicin-Resistant HepG2 Cells

Journal of Natural Products
Xuelin ZhouJohn H K Yeung

Abstract

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 ≈ 7-12 μM), in HepG2 and R-HepG2 cells. Miltirone (1) (1.56-6.25 μM) 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 μM), 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...Continue Reading

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Citations

May 31, 2016·European Journal of Medicinal Chemistry·Gui-Min XueLing-Yi Kong
Sep 1, 2016·Oxidative Medicine and Cellular Longevity·Yu-Chiang HungWen-Long Hu
Jan 19, 2017·International Journal of Molecular Sciences·Dongsheng FanLi-Ping Bai
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Jun 30, 2019·Critical Reviews in Microbiology·Rene Christena LowrenceSaisubramanian Nagarajan

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