葡萄糖代谢紊乱被认为是乳腺癌的发病机制之一。噻吗嗪（TMZ）通过阻断3-酮酰辅酶A硫酰化酶酶活性，抑制了脂肪酸β-氧化，从而增强了葡萄糖氧化和代谢呼吸。本研究旨在研究TMZ在乳腺癌体内外模型中的细胞毒性作用，重点关注其对一些糖酵解酶和AKT信号通路表达的影响。通过不同浓度的TMZ [0.01-100 μM] 对乳腺（MCF-7）癌细胞系进行筛选细胞毒性作用的测试。在体内，通过给小鼠实验性固体艾希氏癌注射分级剂量的TMZ（10、20、30 mg/kg）进行测试。随后，收集肿瘤组织，采用定量PCR检测葡萄糖转运蛋白1（GLUT-1）和糖酵解酶的表达水平。采用免疫组织化学方法检测蛋白质表达的AKT和细胞髓细胞瘤（c-Myc），并将p53表达进行评估。使用Auto-Dock Vina分子对接程序进行TMZ在AKT和c-Myc上的分子对接研究。TMZ显示出对MCF-7细胞有细胞毒性作用，其IC50值为2.95 μM。在体内，TMZ减轻了肿瘤重量，降低了糖酵解酶的表达，抑制了AKT信号传导，但增加了p53的表达。分子对接和体外研究表明，TMZ是一种对AKT和c-Myc选择性抑制剂。总之，TMZ在乳腺癌生物模型中显示出抑制肿瘤增殖的可行方法。版权所有 © 2023. Elsevier B.V. 发布。

Disturbance in glucose metabolism was proposed to be a pathogenetic mechanism of breast cancer. Trimetazidine (TMZ) inhibits β-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 μM]. 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 μM. 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.Copyright © 2023. Published by Elsevier B.V.