Abstract
As a nitric oxide (NO) donor prodrug, JS‐K inhibits cancer cell proliferation, induces the differentiation of human leukaemia cells, and triggers apoptotic cell death in various cancer models. However, the anti‐cancer effect of JS‐K in gastric cancer has not been reported. In this study, we found that JS‐K inhibited the proliferation of gastric cancer cells in vitro and in vivo and triggered mitochondrial apoptosis. Moreover, JS‐K induced a significant accumulation of reactive oxygen species (ROS), and the clearance of ROS by antioxidant reagents reversed JS‐K‐induced toxicity in gastric cancer cells and subcutaneous xenografts. Although JS‐K triggered significant NO release, NO scavenging had no effect on JS‐K‐induced toxicity in vivo and in vitro. Therefore, ROS, but not NO, mediated the anti‐cancer effects of JS‐K in gastric cancer. We also explored the potential mechanism of JS‐K‐induced ROS accumulation and found that JS‐K significantly down‐regulated the core proteins of mitochondria respiratory chain (MRC) complex I and IV, resulting in the reduction of MRC complex I and IV activity and the subsequent ROS production. Moreover, JS‐K inhibited the expression of antioxidant enzymes, including copper‐zinc‐containing superoxide dismutase (SOD1) and catalase, which contributed to the decrease of antioxidant enzymes activity and the subsequent inhibition of ROS clearance. Therefore, JS‐K may target MRC complex I and IV and antioxidant enzymes to exert ROS‐dependent anti‐cancer function, leading to the potential usage of JS‐K in the prevention and treatment of gastric cancer.
Highlights
We found that JS‐K inhibited gastric cancer cell proliferation by blocking the cell cycle at the G2‐M phase and suppressed gastric cancer xenograft growth in nude mice, demonstrating that JS‐ K is effective against gastric cancer
JS‐K significantly inhibits the growth of HL‐60 and OPM1 multiple myeloma cells inoculated subcutaneously in mice.[3,6,29]
The role of JS‐ K in the treatment of orthotopic tumours is controversial because JS‐K inhibited the growth of human hepatoma JM‐1 cells implanted intrahepatically in nude rats[2]; it did not result in tumour growth retardation or extend survival within tracranial U87 rat glioma.[30]
Summary
As a nitric oxide (NO) donor prodrug, JS‐K is activated to release NO upon nucleophilic attack by reduced thiols, such as glutathione (GSH).[13,14] The reaction is catalysed by glutathione‐S‐transferases (GSTs), and JS‐K has been identified as a selective GSTα targeting compound.[3,15] Glutathione‐S‐transferases are phase II detoxification enzymes and catalyse the conjunction of xenobiotics with cellular reduced GSH; overexpression of GST in tumour cells allows tumour cells to gain a selective survival advantage over normal cells to chemotherapeutics by enhanced detoxification through GSH conjunction.[16,17] up‐regulation of GST in tumour cells usually induces multi‐drug resistance, and GSTs have been regarded as potent targets for anti‐cancer drug design and synthesis.[17,18] The design strategy for JS‐K set out to exploit the overexpression of GST in malignant cancer cells compared with that in normal tissue In line with this concept, JS‐K has been reported to FIGURE 1 JS‐K inhibits cell proliferation in different gastric cancer cell lines. Our study identified a potent target and molecular mechanism for JS‐K in mediating ROS‐dependent anti‐neoplastic effects in gastric cancer
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