Curcuminoid WZ26, a TrxR1 inhibitor, effectively inhibits colon cancer cell growth and enhances cisplatin-induced cell death through the induction of ROS

• Published in: Free radical biology & medicine Vol. 141; pp. 93 - 102
• Main Authors: Zhang, Tingting, Zheng, Peisen, Shen, Xin, Shao, Rongrong, Wang, Bin, Shen, Huanpei, Zhang, Jingjing, Xia, Yiqun, Zou, Peng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: Cisplatin; Colon cancer; Reactive oxygen species; Thioredoxin reductase 1; WZ26; DHE; Ser; Reactive oxygen species; DMSO; JNK; Gln; MDA; MTT; WZ26; Glu; Colon cancer; SPR; Gly; Cys; GSH; DTNB; DAB; CI; Lys; SOD; TrxR1; Cisplatin; Thioredoxin reductase 1; Sec; DCFH-DA; NAC; ROS; Ala; Leu
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2019.06.005

Colon cancer is one of the leading causes of cancer-related deaths. Chemotherapy has improved survival in patients with colon cancer, but has a narrow therapeutic window due to its toxicity. Therefore, novel therapies for colon cancer are urgently needed. We previously developed a curcumin analog WZ26 as an anti-cancer agent in pre-clinical evaluation. In the present study, we further explored the mechanism and target of WZ26 in colon cancer cells. Our results show that WZ26 targets thioredoxin reductase 1 (TrxR1) and increases cellular reactive oxygen species (ROS) levels, which results in the activation of JNK signaling pathway in human colon cancer cells. Furthermore, we found that WZ26 significantly enhances cisplatin-induced cell growth inhibition in colon cancer cells. WZ26 combined with cisplatin markedly increases the accumulation of ROS, and thereby induces DNA damage and activation of JNK signaling pathway. Pretreatment with antioxidant N-acetyl-l-cysteine (NAC) significantly abrogates the combined treatment-induced ROS generation, DNA damage and cell death. In addition, the activation of JNK signaling pathway prompted by WZ26 and cisplatin was also reversed by NAC pretreatment. In vivo, WZ26 combined with cisplatin significantly inhibits tumor growth in a colon cancer xenograft model. Remarkably, WZ26 attenuates the body weight loss evoked by cisplatin treatment. This study discloses a previously unrecognized mechanism underlying the biological activity of WZ26, and reveals that WZ26 and cisplatin combinational treatment might potentially become a more effective regimen in colon cancer therapy. [Display omitted] •WZ26 directly binds TrxR1 in vitro and inactivates TrxR1 in human colon cancer cells.•WZ26 displays synergistic lethality with erastin against colon cancer cells.•WZ26 and cisplatin cooperated to trigger ROS-dependent cell death in colon cancer cells.•WZ26 and cisplatin combination inhibits HCT116 xenograft tumor growth in vivo.