Danya Zhang , Yuxin Chen , Yue Sun , Hanjie Xu , Rui Wei , Ying Zhou , Fei Li , Jie Li , Jing Wang , Pingbo Chen , Ling Xi
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引用次数: 0
Abstract
Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities. However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis. Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment.
期刊介绍:
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.