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


CONCLUSIONS
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.
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.
El-shaimaa A
el-SA
Arafa
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.
Ahmed H
AH
Abdelazeem
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.
Hany H
HH
Arab
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.
Hany A
HA
Omar
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C583117:OSU-CG5; D013267:Stilbenes; D045162:Thiazolidinediones; D005947:Glucose; D000077185:Resveratrol