| Gastric cancer is the common malignant tumor of digestive tract,and it has been a serious threat to people’s physical and mental health.Chemotherapy,as an important part of comprehensive treatment,plays an important role in alleviating symptoms and prolonging survival in patients with gastric cancer.However,severe side effects and complications of traditional anti-gastric cancer drugs,such as cisplatin and 5-fluorouracil,become major problems in the clinical setting.Therefore,the discovery of new strategies,targets and drug candidates for the treatment of gastric cancer is of great significance.Curcumin,a yellow compound isolated from the rhizome of the herb Curcuma longa L,has been demonstrated as a multifunctional bioactive natural product.However,clinical application of curcumin is limited by its poor bioavailability and pharmacokinetic profile.The results indicated that WZ35 was more stable than curcumin in vitro.WZ35 showed much stronger anti-proliferative effects than curcumin in gastric cancer cells.Mechanistically,the results indicated that WZ35 induced ROS production,resulting in the activation of ER stress apoptotic pathway and eventually cell apoptosis in SGC-7901 cells.Blockage of ROS production completely reversed WZ3 5-induced ER stress activation as well as cancer cell apoptosis.Diphenyl difluoroketone(EF24),a molecule having structural similarity to curcumin,exhibits potent anti-tumor activities by arresting cell cycle and inducing apoptosis.Although EF24 demonstrates potent anticancer efficacy in numerous types of human cancer cells,the cellular targets of EF24 have not been fully defined.The results indicated that EF24 primarily targets the Sec residue of the antioxidant enzyme TrxRl to inhibit its Trx-reduction activity,but further elicits a new function of generating reactive oxygen species.Accumulation of ROS disrupts the intracellular redox balance,activates ER stress and eventually induces apoptosis in gastric cancer cells.Piperlongumine,a natural product isolated from the long pepper Piper longum L,was recently identified as selectively toxic to cancer cells in vitro and in vivo.Piperlongumine treatment increases ROS levels several folds in cancer cells but not in normal cells,which may underlie the selective cancer cell-killing action of piperlongumine.Until now,how piperlongumine increases cellular ROS remains unclear.The results indicated TrxR1 is a target of piperlongumine,both in vitro and in vivo,and demonstrated that piperlongumine induces apoptotic cell death through ROS-mediated ER-stress and mitochondrial dysfunction.Furthermore,it was found that TrxR1 was significantly up-regulated,at both the protein levels and activity in gastric cancer cell lines and clinically obtained gastric cancer tissues.At present,the severe side effects and complications such as hematological and gastrointestinal toxicities of current anti-gastric cancer drugs become major problems in the clinical setting.Drug ’repurposing’ is the identification of new therapeutic applications for drugs that have received US FDA approval for another purpose.Due to the reduced length and cost of research and trial phases,drug repurposing is more affordable and achievable than novel drug discovery.The results indicated that AF showed strong anti-proliferative effects towards human gastric cancer cells.Mechanistically,it was found that AF induced ROS production,resulting in the activation of ER stress apoptotic pathway and eventually cell apoptosis in gastric cancer cells.Taken together,this study suggested that WZ35 can induce cell apoptosis by increasing ROS production,and discovered TrxRl was the target of EF24 and piperlongumine.Furthermore,it was found that TrxRl was significantly up-regulated in gastric cancer cell lines and clinically obtained gastric cancer tissues,and the anti-cancer activity of auranofin on gastric cancer cells was further identified.More importantly,these results indicated that TrxRl is a potential target for gastric cancer therapy. |
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