El-shaimaa A Arafa1, Ahmed H Abdelazeem2, Hany H Arab3, Hany A Omar1. 1. 1] Department of Pharmacology, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia [2] Department of Pharmacology and Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. 2. 1] Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia [2] Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. 3. 1] Department of Pharmacology, College of Pharmacy, Taif University, Taif 21974, Saudi Arabia [2] Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
Abstract
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.
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 humancolorectal 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.
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