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Allylated Curcumin Analog CA6 Inhibits TrxR1 and Leads to ROS-Dependent Apoptotic Cell Death in Gastric Cancer Through Akt-FoxO3a

Authors Rajamanickam V, Yan T, Wu L, Zhao Y, Xu X, Zhu H, Chen X, Wang M, Liu Z, Liu Z, Liang G, Wang Y

Received 15 August 2019

Accepted for publication 26 November 2019

Published 13 January 2020 Volume 2020:12 Pages 247—263

DOI https://doi.org/10.2147/CMAR.S227415

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Nakshatri


Vinothkumar Rajamanickam,* Tao Yan,* Liangrong Wu, Yanni Zhao, Xiaohong Xu, Heping Zhu, Xi Chen, Meihong Wang, Zhoudi Liu, Zhiguo Liu, Guang Liang, Yi Wang

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yi Wang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, People’s Republic of China
Tel/Fax +86- 577-85773060
Email yi.wang1122@wmu.edu.cn

Background: Gastric cancer is one of the leading causes of cancer-related deaths. Allylated monocarbonyl analogs of curcumin (MACs) have been reported to selectively inhibit a broad range of human cancers including gastric cancer. However, the precise molecular mechanisms underlying the inhibitory activities of MACs are not fully known.
Methods: In this study, we examined the anti-tumor activities of an allylated MAC, CA6, on gastric cancer cells and gastric cancer xenograft mouse model. The potential molecular anti-tumor mechanisms of CA6 were also elucidated.
Results: Our data show that CA6 exhibited significant cytotoxicity in gastric cancer cells, which was seen as an induction of G2/M cell cycle arrest and apoptosis. These activities were mediated through an elaboration of ROS levels in gastric cancer cells and induction of endoplasmic reticulum stress. CA6 increased ROS levels through directly binding to and inhibiting thioredoxin reductase R1 (TrxR1). Also, CA6-generated ROS inhibited Akt and activated forkhead O3A (FoxO3a), causing cytotoxicity in gastric cancer cells. Finally, CA6 treatment dose-dependently reduced the growth of gastric cancer xenografts in tumor-bearing mice, which was associated with reduced TrxR1 activity and increased ROS in the tumor.
Conclusion: In summary, our studies demonstrate that CA6 inhibited gastric cancer growth by inhibiting TrxR1 and increasing ROS, which in turn activated FoxO3a through suppressing Akt. CA6 is a potential candidate for the treatment of gastric cancer.

Keywords: gastric cancer, curcumin analog, reactive oxygen species, TrxR1, FOXO3a

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