Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

• 作者: Dingyuan Ma Jun Chen Lin An Liying Peng Ningyuan Sun Ping Zhang Weiwei Tang Xiaowei Zhang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（8）
• 所属期刊栏目: Original articles
• 页码范围: 1397-1413
• 页数: 17页
• 语种: 英文

摘要

Pyroptosis is a form of programmed cell death,and recently described as a new molecular mechanism of chemotherapy drugs in the treatment of tumors.Miltirone,a derivative of phenanthrenequinone isolated from the root of Salvia miltiorrhiza Bunge,has been shown to possess anti-cancer activities.Here,we found that miltirone inhibited the cell viability of either HepG2 or Hepal-6 cells,and induced the proteolytic cleavage of gasdermin E (GSDME) in each hepatocellular carcinoma (HCC) cell line,with concomitant cleavage of caspase 3.Knocking out GSDME switched miltirone-induced cell death from pyroptosis to apoptosis.Additionally,the induction effects of miltirone on GSDME-dependent pyroptosis were attenuated by siRNA-mediated caspase three silencing and the specific caspase three inhibitor Z-DEVD-FMK,respectively.Miltirone effectively elicited intracellular accumulation of reactive oxygen species (ROS),and suppressed phosphorylation of mitogen-activated and extracellular signal-regulated kinase (MEK) and extracellular regulated protein kinases 1/2 (ERK1/2) for pyroptosis induction.Moreover,miltirone significantly inhibited tumor growth and induced pyroptosis in the Hepal-6 mouse HCC syngeneic model.These results provide a new insight that miltirone is a potential therapeutic agent for the treatment of HCC via GSDME-dependent pyroptosis.