OSU-CG5, a novel energy restriction mimetic agent, targets human colorectal cancer cells in vitro

Aim： Energy-restriction mimetic agents （ERMAs） are small-molecule agents that target various aspects of energy metabolism, which has emerged as a promising approach in cancer therapy. In the current study, we tested the ability of OSU-CGS, a novel ERMA, to tar- get human colorectal cancer （CRC） in vitro. Methods： Two human CRC cell lines （HCT-116 and Caco-2） were tested. Cell viability was assessed using MTT assay. Caspase-3/7 activities were measured using Caspase-GIo 3/7 assay kit. Western blot analysis was used to measure the expression of relevant pro- teins in the cells. Glucose consumption of the cells was detected using glucose uptake cell-based assay kit. Results： OSU-CG5 dose-dependently inhibited HCT-116 and Caco-2 cell proliferation with the ICso values of 3.9 and 4.6 μmol/L, respec- tively, which were 20-25-fold lower than those of resveratrol, a reference ERMA. Both OSU-CG5 （5, 10, and 20 μmol/L） and resvera- trol （50, 100, and 200 μmol/L） dose-dependently increased caspase-3/7 activity and PARP level in the cells. Furthermore, both OSU- CG5 and resveratrol induced dose-dependent energy restriction in the cells： they suppressed glucose uptake and Akt phosphoryla- tion, decreased the levels of p-mTOR and p-pTOS6K, increased the levels of ER stress response proteins GRP78 and GADD153, and increased the level of β-TrCP, which led to the downregulation of cyclin D1 and Spl. Conclusion： OSU-CG5 exhibits promising anti-cancer activity against human CRC cells in vitro, which was, at least in part, due to energy restriction and the consequent induction of ER stress and apoptosis.