Antitumor effect of trimetazidine in a model of solid Ehrlich carcinoma is mediated by inhibition of glycolytic pathway and AKT signaling

Disturbance in glucose metabolism was proposed to be a pathogenetic mechanism of breast cancer. Trimetazidine (TMZ) inhibits 13-oxidation of fatty acids through blocking the activity of 3-ketoacylCoA thiolase enzyme, leading to enhancement of glucose oxidation and metabolic respiration. The present study aimed to examine the cytotoxic effect of TMZ in both in vivo and in vitro models of breast cancer, focusing on its impact on the expression of some glycolytic enzymes and AKT signaling. The cytotoxic effect of TMZ was screened against breast (MCF-7) cancer cell line at different concentrations [0.01-100 & mu;M]. In vivo, graded doses (10, 20, 30 mg/ kg) of TMZ were tested against solid Ehrlich carcinoma (SEC) in mice. Tumor tissues were isolated for assessment of the expression of glucose transporter-1 (GLUT-1) and glycolytic enzymes by quantitative PCR. The protein expression of AKT and cellular myelocytomatosis (c-Myc) was determined by western blotting, while p53 expression was evaluated by immunohistochemistry. Molecular docking study of TMZ effect on AKT and c-Myc was performed using Auto-Dock Vina docking program. TMZ showed a cytotoxic action against MCF-7 cells, having IC50 value of 2.95 & mu;M. In vivo, TMZ reduced tumor weight, downregulated the expression of glycolytic enzymes, suppressed AKT signaling, but increased p53 expression. Molecular docking and in silico studies proposed that TMZ is an AKT and c-Myc selective inhibitor. In conclusion, TMZ demonstrated a viable approach to suppress tumor proliferation in biological models of breast cancer.

Automated summary

This study aimed to examine the cytotoxic effect of trimetazidine (TMZ) on breast cancer cells and its impact on glycolytic enzymes and AKT signaling. The study found that TMZ can inhibit fatty acid β-oxidation, leading to enhanced glucose oxidation and metabolic respiration. TMZ has a cytotoxic effect on breast cancer cells, reduces tumor weight, and suppresses AKT signaling.