Original Article

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

Authors: El-shaimaa A Arafa, Ahmed H Abdelazeem, Hany H Arab, Hany A Omar
DOI: 10.1038/aps.2013.183


El-shaimaa A ARAFA1, 3, Ahmed H ABDELAZEEM2, 4, Hany H ARAB1, 5, Hany A OMAR1, 3, *
1Department of Pharmacology and 2Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia; 3Department of Pharmacology and 4Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; 5Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt

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-CG5, a novel ERMA, to target 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-Glo 3/7 assay kit. Western blot analysis was used to measure the expression of relevant proteins 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 IC50 values of 3.9 and 4.6 μmol/L, respectively, which were 20–25-fold lower than those of resveratrol, a reference ERMA. Both OSU-CG5 (5, 10, and 20 μmol/L) and resveratrol (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 phosphorylation, decreased the levels of p-mTOR and p-p70S6K, 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 Sp1.

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.

Keywords: colorectal cancer; energy restriction mimetic agent; OSU-CG5; resveratrol; apoptosis; glucose uptake; Akt; mTOR; ER stress; β-TrCP

The current work was supported by grant No 1-434-2863 from the Deanship of Scientific Research, Taif University, Saudi Arabia. The authors would like to thank Dr Ching-shih CHEN at the Ohio State University for his insightful discussion and suggestions on the manuscript.
* To whom correspondence should be addressed.
E-mail omar.22@buckeyemail.osu.edu
Received 2013-09-29 Accepted 2013-11-27

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