Curcuminoid WZ35 synergize with cisplatin by inducing ROS production and inhibiting TrxR1 activity in gastric cancer cells

Abstract

Background Cisplatin is one of the most widely used chemotherapeutic agents, but its efficacy is limited by its side effects. Hence, it is of great significance to develop novel agents to synergize with cisplatin and decrease side effects. In our previous study, we demonstrated that WZ35, a novel curcumin analogue, exhibited potent anti-cancer effects in vitro and in vivo. Here, we investigated whether WZ35 synergize to potentiate cisplatin activity in gastric cancer cells. Methods Cell apoptosis and cellular ROS levels were analyzed by flow cytometry. TrxR1 activity in gastric cells or tumor tissues was determined by the endpoint insulin reduction assay. Western blot was used to analyze the levels of indicated molecules. Nude mice xenograft model was used to test the effects of WZ35 and cisplatin combination on gastric cancer cell growth in vivo. Results We found that WZ35 significantly enhanced cisplatin-induced cell growth inhibition and apoptosis in gastric cancer cells. Further mechanism study showed that WZ35 synergized the anti-tumor effects of cisplatin by inhibiting TrxR1 activity. By inhibiting TrxR1 activity, WZ35 combined with cisplatin markedly induced the production of ROS, activated p38 and JNK signaling pathways, and eventually induced apoptosis of gastric cancer cells. In vivo, WZ35 combined with cisplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, WZ35 attenuated the body weight loss evoked by cisplatin treatment. Conclusion This study elucidated the underlying mechanisms of synergistic effect of WZ35 and cisplatin, and suggest that such a combinational treatment might potentially become a more effective regimen in gastric cancer therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1215-y) contains supplementary material, which is available to authorized users.

Plumbagin Enhances the Anticancer Efficacy of Cisplatin by Increasing Intracellular ROS in Human Tongue Squamous Cell Carcinoma

“…Oxidative Medicine and Cellular Longevity CDDP-induced apoptosis, and antioxidants can eliminate its cytotoxic effects [45]. He et al showed that Curcuminoid WZ35 exerted a synergistic effect with cisplatin on inducing ROS production in gastric cancer [46]. Therefore, we explored whether ROS participate in the synergistic effect of PLB and CDDP.…”

Kirenol inhibited the cell survival and induced apoptosis in human thyroid cancer cells by altering PI3K/AKT and MAP kinase signaling pathways

“…Similarly a study conducted using Curcuminoid WZ35 exerted a mutual effect with cancer drug cisplatin by inducing ROS level in gastric cancer 20 . With thorough literature Studies it is suggested that activation of ROS/JNK and inhibition of the PI3K/AKT signaling pathway in cancer may effectively induce apoptosis and inhibits cell survival 21‐24 .…”

A trienone analog of curcumin, 1,7-bis(3-hydroxyphenyl)-1,4,6-heptatrien-3-one, possesses ROS- and caspase-mediated apoptosis in human oral squamous cell carcinoma cells in vitro

“…ROS-metabolic enzymes have been proposed as the main biological targets of curcuminoids. Curcuminoids and analogs can bind to several ROS-metabolic enzymes including carbonyl reductase 1, glutathione-S-transferase, glyoxalase I, NAD(P)H dehydrogenase, quinone 1, and thioredoxin reductase 1 (TrxR1), thereby inactivating the enzymes and leading to ROS accumulation [16,36]. Additionally, a differential ROS-inducing ability was related, in part, to the compound's structure.…”

“…Synthetic curcuminoid derivatives have, therefore, been developed by modifying the parent structure to improve anticancer potency. These analogs include DK1 [13], B63 [14], EF24 [15], WZ35 [16], and those with 1,4,6-trien-one function or trienones [17].…”