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

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 phenanthrene-quinone isolated from the root of Salvia miltiorrhiza Bunge, has been shown to possess anti-cancer activities....

Full description

Saved in:
Bibliographic Details
Published in:Acta pharmaceutica Sinica. B 2020-08, Vol.10 (8), p.1397-1413
Main Authors: Zhang, Xiaowei, Zhang, Ping, An, Lin, Sun, Ningyuan, Peng, Liying, Tang, Weiwei, Ma, Dingyuan, Chen, Jun
Format: Article
Language:English
Subjects:
Cell death
GSDME
Hepa1-6
Hepatocellular carcinoma
HepG2
Miltirone
Original
Pyroptosis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 phenanthrene-quinone 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 Hepa1-6 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 Hepa1-6 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. Miltirone might be a potential candidate agent for the treatment of HCC. A central signaling axis, ROS/ERK1/2–BAX–caspase 9–caspase 3–gasdermin E (GSDME), was demonstrated to regulate the miltirone-induced pyroptotic process [Display omitted]
ISSN:2211-3835
2211-3843
DOI:10.1016/j.apsb.2020.06.015