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

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Miltirone Is a Dual Inhibitor of P-Glycoprotein and Cell Growth in Doxorubicin-Resistant HepG2 Cells
Journal of Natural Products ( IF 3.3 ) Pub Date : 2015-09-04 00:00:00 , DOI: 10.1021/acs.jnatprod.5b00516
Xuelin Zhou ₁ , Yan Wang ₁ , Wayne Y. W. Lee ₁ , Penelope M. Y. Or ₁ , David C. C. Wan ₁ , Yiu Wa Kwan ₁ , John H. K. Yeung ₁

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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.

中文翻译：

Miltirone是抗阿霉素的HepG2细胞中P-糖蛋白和细胞生长的双重抑制剂

Miltirone（1）是一种从丹参丹参中分离出的松果油型二萜醌，在过表达p-糖蛋白（P-gp）的人类癌细胞中具有抗癌活性。目前的研究结果表明，米替龙对人肝癌HepG2细胞系及其过表达P-gp的阿霉素抗性对应物（R-HepG2）的P-gp抑制和凋亡诱导具有双重作用。Miltirone（1）引发的浓度依赖性细胞毒性，具有相似的效力（EC ₅₀ ≈7-12μM），在HepG2和R-HepG2细胞。米替农（1）（1.56-6.25μM）对阿霉素（DOX）诱导的R-HepG2生长抑制产生协同作用（协同作用：0.3 <结合指数<0.5）。分子对接研究表明，miltirone（1）与P-gp的活性位点相互作用的结合亲和力高于DOX，表明它是P-gp抑制剂。流式细胞仪分析证实了米替龙（1）是P-gp的竞争性抑制剂。在非坏死浓度（1.56–25μM）下，米替农（1）激活caspase依赖性凋亡途径并触发了活性氧（ROS）和ROS介导的丝裂原活化蛋白激酶（MAPK）信号传导途径的生成（例如p38 MAPK，应激活化蛋白激酶/ c-Jun N-末端激酶和HepG2和R-HepG2细胞中的细胞外调节激酶1/2）。因此，我们得出的结论是，miltirone（1）是人耐药肝细胞中P-gp和细胞生长的双重抑制剂。

更新日期：2015-09-04

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