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

Abstract

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 antitumor 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.

Gastroprotective effects of water extract of domesticated Amauroderma rugosum against several gastric ulcer models in rats

“… 2014 ; Rajamanickam et al. 2020 ). Moreover, TNF-α can induce the immune response to generate cytotoxic metabolites, suppress gastric microcirculation and delay the recovery (Verma and Kumar 2016 ).…”

Curcumin and cancer biology: Focusing regulatory effects in different signalling pathways

“…In vitro and in vivo studies also demonstrated that allylated MAC (curcumin analogue) and CA6, blocked the development of gastric cancer cells. Specifically, CA6 binds directly to TrxR1 and inhibits its activity, resulting in ROS aggregation in gastric cancer cells (Rajamanickam et al, 2020)…”

<p>Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells</p>

“…Various anticancer agents have been shown to promote ROS generation in cancer cells. 32,33 Study by Rajamanickam et al 20 indicates that allylated curcumin analog CA6 directly binds to and inhibiting the activity of TrxR1 resulting in the increase of ROS. Others suggest that Chinese chemical like ginsenoside Rh4, Luteolin may disturb the mitochondria function to promote the production of ROS.…”

“…13 Studies had demonstrated that targeting the oxidative stress-mediated ER stress is one of the effective strategies for tumor therapy. [18][19][20] Yang et al 18 found that ω-Hydroxyundec-9-enoic acid induced apoptosis through ROS-mediated endoplasmic reticulum stress in non-small cell lung cancer cells. Wu et al 19 indicated that bicyclol exerted an anti-tumor effect via ROS-mediated ER stress in human renal cell carcinoma cells.…”

“…Wu et al 19 indicated that bicyclol exerted an anti-tumor effect via ROS-mediated ER stress in human renal cell carcinoma cells. Rajamanickam et al 20 suggested that allylated curcumin analog CA6 inhibited proliferation of gastric cancer cells though ROS-ER stress axis. However, the effect of TN on the ROS-ER stress axis remained unclear.…”