Min Yeong Kim, Hee-Jae Cha, Su Hyun Hong, Sung-Kwon Moon, Taeg Kyu Kwon, Young-Chae Chang, Gi Young Kim, Jin Won Hyun, A-Young Nam, Jung-Hyun Shim, Yung Hyun Choi
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引用次数: 0
Abstract
Cynaropicrin, a sesquiterpene lactone found in artichoke leaves exerts diverse pharmacological effects. This study investigated whether cynaropicrin has a paraptosis-like cell death effect in human hepatocellular carcinoma Hep3B cells in addition to the apoptotic effects reported in several cancer cell lines. Cynaropicrin-induced cytotoxicity and cytoplasmic vacuolation, a key characteristic of paraptosis, were not ameliorated by inhibitors of necroptosis, autophagy, or pan caspase inhibitors in Hep3B cells. Our study showed that cynaropicrin-induced cytotoxicity was accompanied by mitochondrial dysfunction and endoplasmic reticulum stress along with increased cellular calcium ion levels. These effects were significantly mitigated by endoplasmic reticulum stress inhibitor or protein synthesis inhibitor. Moreover, cynaropicrin treatment in Hep3B cells increased reactive oxygen species generation and downregulated apoptosis-linked gene 2-interacting protein X (Alix), a protein that inhibits paraptosis. The addition of the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) neutralized cynaropicrin-induced changes in Alix expression and endoplasmic reticulum stress marker proteins counteracting endoplasmic reticulum stress and mitochondrial impairment. This demonstrates a close relationship between endoplasmic reticulum stress and reactive oxygen species generation. Additionally, cynaropicrin activated p38 mitogen activated protein kinase and a selective p38 mitogen activated protein kinase blocker alleviated the biological phenomena induced by cynaropicrin. NAC pretreatment showed the best reversal of cynaropicrin induced vacuolation and cellular inactivity. Our findings suggest that cynaropicrin induced oxidative stress in Hep3B cells contributes to paraptotic events including endoplasmic reticulum stress and mitochondrial damage.
期刊介绍:
Biomolecules & Therapeutics (Biomolecules & Therapeutics) (Print ISSN 1976-9148, Online ISSN 2005-4483) is an international, peer-reviewed, open access journal that covers pharmacological and toxicological fields related to bioactive molecules and therapeutics. It was launched in 1993 as "The Journal of Applied Pharmacology (ISSN 1225-6110)", and renamed "Biomolecules & Therapeutics" (Biomol Ther: abbreviated form) in 2008 (Volume 16, No. 1). It is published bimonthly in January, March, May, July, September and November. All manuscripts should be creative, informative, and contribute to the development of new drugs. Articles in the following categories are published: review articles and research articles.