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

Xiaowei Zhang1,2, Ping Zhang1,2, Lin An1,2

  • 1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

Acta Pharmaceutica Sinica. B
|September 23, 2020
PubMed

Insights

Miltirone, derived from Salvia miltiorrhiza, triggers programmed cell death (pyroptosis) in liver cancer cells by activating gasdermin E (GSDME). This compound shows potential as a novel chemotherapy for hepatocellular carcinoma (HCC).

Area of Science:

  • Oncology
  • Cell Biology
  • Pharmacology

Background:

  • Pyroptosis is a programmed cell death pathway implicated in cancer therapy.
  • Miltirone, a phenanthrene-quinone derivative from Salvia miltiorrhiza, exhibits anti-cancer properties.
  • Understanding novel mechanisms of chemotherapy is crucial for effective tumor treatment.

Purpose of the Study:

  • To investigate the anti-cancer mechanism of miltirone in hepatocellular carcinoma (HCC).
  • To determine if miltirone induces pyroptosis and its role in HCC cell death.
  • To explore miltirone's therapeutic potential for HCC treatment.

Main Methods:

  • Assessed miltirone's effect on HepG2 and Hepa1-6 cell viability.
  • Analyzed gasdermin E (GSDME) and caspase-3 cleavage.
  • Utilized GSDME knockout cells and siRNA for caspase-3 inhibition.
  • Measured reactive oxygen species (ROS) and MEK/ERK signaling pathways.
  • Evaluated miltirone's efficacy in a mouse HCC syngeneic model.

Main Results:

  • Miltirone inhibited HCC cell viability and induced GSDME and caspase-3 cleavage, characteristic of pyroptosis.
  • GSDME knockout switched miltirone-induced cell death to apoptosis.
  • Miltirone-induced pyroptosis was dependent on caspase-3 activity.
  • Miltirone increased ROS levels and suppressed MEK/ERK phosphorylation.
  • Miltirone inhibited tumor growth and promoted pyroptosis in vivo.

Conclusions:

  • Miltirone induces hepatocellular carcinoma cell death through GSDME-dependent pyroptosis.
  • The anti-cancer effects of miltirone involve ROS generation and MEK/ERK pathway inhibition.
  • Miltirone represents a potential therapeutic agent for HCC via pyroptosis induction.
Keywords:
7-AAD, 7-aminoactinomycin DAKT, AKT serine/threonine kinase, also known as protein kinase BANOVA, analysis of varianceBAX, BCL2-associated XCCK-8, cell counting kit-8CRISPR, clustered regularly interspaced short palindromic repeatsCas9, caspase 9Cell deathDCFH-DA, dye 2,7-dichlorofluoresce diacetateDMEM, Dulbecco's modified Eagle's mediumDMSO, dimethyl sulfoxideECL, enhanced chemiluminescenceERK1/2, extracellular regulated protein kinases 1/2FBS, fetal bovine serumFITC, fluorescein isothiocyanateGAPDH, glyceraldehyde-3-phosphate dehydrogenaseGSDMD, gasdermin DGSDMEGSDME, gasdermin EH&E, hematoxylin and eosinHCC, hepatocellular carcinomaHRP, horseradish peroxidaseHepG2Hepa1-6Hepatocellular carcinomaIC50, the half maximal inhibitory concentrationIgG (H + L), immunoglobulin G (heavy chain + light chain)KO, knockoutLDH, lactic dehydrogenaseMEK, mitogen-activated and extracellular signal-regulated kinaseMEM, minimum essential mediumMMP, mitochondrial membrane potentialMS, mass spectrumMiltironeN-GSDME, N-terminal GSDMENAC, N-acetyl cysteineNC, negative controlNMR, nuclear magnetic resonanceNS, no significancePARP, poly ADP-ribose polymerasePBS, phosphate-based bufferPI, propidium iodidePI3K, phosphatidylinositol 3-kinasePyroptosisRIPA, radioimmunoprecipitation assayROS, reactive oxygen speciesSD, standard deviationSDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresisTBST, Tris-buffered saline with Tween solutionTCGA, the Cancer Genome AtlasVEGF, vascular endothelial growth factorgRNA, guide RNAi.p., intraperitoneali.v., intravenousmTOR, mammalian target of rapamycinp-AKT, phosphorylated-AKTp-ERK1/2, phosphorylated-ERK1/2p-MEK, phosphorylated-MEK

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