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

Author:
Zhou, Xuelin, Wang, Yan, Lee, Wayne Y. W., Or, Penelope M. Y., Wan, David C. C., Kwan, Yiu Wa, Yeung, John H. K.
Source:
Journal of natural products 2015 v.78 no.9 pp. 2266-2275
ISSN:
1520-6025
Subject:
P-glycoproteins, Salvia miltiorrhiza, active sites, antineoplastic activity, apoptosis, binding capacity, cell growth, cytotoxicity, diterpenoids, doxorubicin, drug resistance, flow cytometry, growth retardation, hepatoma, human cell lines, humans, median effective concentration, mitogen-activated protein kinase, molecular models, neoplasm cells, signal transduction, synergism
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-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.
Agid:
5498337