Azoxystrobin Induces Apoptosis of Human Esophageal Squamous Cell Carcinoma KYSE-150 Cells through Triggering of the Mitochondrial Pathway

Abstract

Recent studies indicate that mitochondrial pathways of apoptosis are potential chemotherapeutic target for the treatment of esophageal cancer. Azoxystrobin (AZOX), a methoxyacrylate derived from the naturally occurring strobilurins, is a known fungicide acting as a ubiquinol oxidation (Qo) inhibitor of mitochondrial respiratory complex III. In this study, the effects of AZOX on human esophageal squamous cell carcinoma KYSE-150 cells were examined and the underlying mechanisms were investigated. AZOX exhibited inhibitory effects on the proliferation of KYSE-150 cells with inhibitory concentration 50% (IC50) of 2.42 μg/ml by 48 h treatment. Flow cytometry assessment revealed that the inhibitory effect of AZOX on KYSE-150 cell proliferation occurred with cell cycle arrest at S phase and increased cell apoptosis in time-dependent and dose-dependent manners. Cleaved poly ADP ribose polymerase (PARP), caspase-3 and caspase-9 were increased significantly by AZOX. It is worth noted that the Bcl-2/Bax ratios were decreased because of the down-regulated Bcl-2 and up-regulated Bax expression level. Meanwhile, the cytochrome c release was increased by AZOX in KYSE-150 cells. AZOX-induced cytochrome c expression and caspase-3 activation was significantly blocked by Bax Channel Blocker. Intragastric administration of AZOX effectively decreased the tumor size generated by subcutaneous inoculation of KYSE-150 cells in nude mice. Consistently, decreased Bcl-2 expression, increased cytochrome c and PARP level, and activated caspase-3 and caspase-9 were observed in the tumor samples. These results indicate that AZOX can effectively induce esophageal cancer cell apoptosis through the mitochondrial pathways of apoptosis, suggesting AZOX or its derivatives may be developed as potential chemotherapeutic agents for the treatment of esophageal cancer.

Essential Oil Derived From Eupatorium adenophorum Spreng. Mediates Anticancer Effect by Inhibiting STAT3 and AKT Activation to Induce Apoptosis in Hepatocellular Carcinoma

“…Bcl-2 family (including Bcl-2 and Bax) regulates intrinsic apoptosis senses of death signals ( Fox and MacFarlane, 2016 ). Previous studies have reported that the balance of Bcl-2/Bax determines the initiation of mitochondrial apoptosis, and a high ratio of Bcl-2/Bax is considered anti-apoptotic ( Shi et al, 2017 ). Caspase-9 and caspase-3 play the executioner role in apoptosis, and upon their activation, their precursor forms are cleaved ( Lopez and Tait, 2015 ).…”

Daidzein induces choriocarcinoma cell apoptosis in a dose-dependent manner via the mitochondrial apoptotic pathway

“…Equol, which is a metabolite of daidzein, induces apoptosis in SMMC-7721 human hepatocellular carcinoma cells through the intrinsic and endoplasmic reticulum stress pathways (26). Caspase-9 and the Bcl-2/Bax ratio are commonly used activity markers of the mitochondrial apoptotic pathway (43)(44)(45). In the present study, western blotting was used to detect these markers, revealing that the cleavage of caspase-9 increased and the ratio of Bcl-2/Bax decreased in both cell lines in a dose-dependent manner, which indicated that daidzein-induced apoptosis was mediated via the mitochondrial apoptotic pathway.…”

A biflavonoid‐rich extract from Selaginella moellendorffii Hieron. induces apoptosis via STAT3 and Akt/NF‐κB signalling pathways in laryngeal carcinoma

“…32,35 A ratio of Bcl-2/Bax was usually use as the basis for determining apoptosis, and an increased ratio represents anti-cell apoptosis. 36 The Bcl-2 family controls the release of cytochrome c (Cyt-c) by modulating the mitochondrial membrane permeability. 29 Caspases are a group of proteases that have a similar structure in the cyto- (Figure 7).…”

“…The intrinsic apoptotic pathway (the mitochondrial pathway) is regulated by Bcl‐2 protein family (including anti‐apoptotic protein Bcl‐2 and pro‐apoptotic protein Bax) 32,35 . A ratio of Bcl‐2/Bax was usually use as the basis for determining apoptosis, and an increased ratio represents anti‐cell apoptosis 36 . The Bcl‐2 family controls the release of cytochrome c (Cyt‐c) by modulating the mitochondrial membrane permeability 29 .…”