【摘 要】
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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 d
【机 构】
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State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;De
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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.
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