Tayel Fekria, Mahfouz Magdy E, Salama Afrah F, Mansour Mohammed A
Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt.
Zoology Department, Faculty of Science, Kafrelsheikh University, Kafr El Sheikh 33516, Egypt.
Biomedicines. 2021 Oct 23;9(11):1526. doi: 10.3390/biomedicines9111526.
Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene and by a significant increase in the expression of apoptotic genes ( and ). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.
癌细胞表现出更高的糖酵解速率以产生ATP（瓦伯格效应），从而维持更高的增殖速率。在肿瘤细胞中，丙酮酸在三羧酸循环中的氧化被乳酸生成所取代，这一过程由乳酸脱氢酶（LDH）催化。在本研究中，我们使用乙氧喹（EQ）作为一种新型抑制剂来靶向小鼠艾氏腹水癌（EAC）中的LDH，并作为联合疗法来提高传统化疗药物顺铂（CIS）的治疗效果。我们研究了EQ对荷EAC小鼠的抗肿瘤作用，并检查EQ是否能维持CIS的抗肿瘤潜力以及它是否影响LDH活性。EQ治疗对EAC具有明显的抗肿瘤作用，这表现为抗凋亡基因表达显著降低以及凋亡基因（ 和 ）表达显著增加。EQ还导致EAC细胞的自噬活性显著降低，表现为自噬体标志物荧光强度降低。此外，EQ恢复了荷EAC小鼠改变的血液学和生化参数，并改善了受损的肝组织。EQ与CIS联合给药对EAC显示出最高的抗肿瘤效果。总体而言，我们的研究结果表明EQ是癌细胞中LDH的新型抑制剂，也是一种能提高顺铂疗效的联合用药。需要进一步研究以在不同癌症模型和临床试验中验证这种治疗策略。
