Sever Tolga, Ellidokuz Ender Berat, Basbinar Yasemin, Ellidokuz Hulya, Yilmaz Ömer H, Calibasi-Kocal Gizem
Department of Translational Oncology, Institute of Health Sciences, Dokuz Eylul University, 35340 Izmir, Turkey.
Department of Internal Diseases, Gastroenterology, Faculty of Medicine, Dokuz Eylul University, 35340 Izmir, Turkey.
Cancers (Basel). 2023 Dec 6;15(24):5724. doi: 10.3390/cancers15245724.
Deregulation of cellular metabolism has recently emerged as a notable cancer characteristic. This reprogramming of key metabolic pathways supports tumor growth. Targeting cancer metabolism demonstrates the potential for managing colorectal cancer. Beta-hydroxybutyrate (BOHB) acts as an acetyl-CoA source for the tricarboxylic acid (TCA) cycle, possibly redirecting energy metabolic pathways towards the TCA cycle that could enhance sensitivity to oxaliplatin, through the generation of reactive oxygen species (ROS). This study explores the potential of BOHB to enhance oxaliplatin's cytotoxic effect by altering the energy metabolism in colorectal cancer. The study employed advanced in vitro organoid technology, which successfully emulates in vivo physiology. The combination treatment efficacy of BOHB and oxaliplatin was evaluated via cell viability assay. The levels of key proteins involved in energy metabolism, apoptotic pathways, DNA damage markers, and histone acetylation were analyzed via Western Blot. ROS levels were evaluated via flow cytometer. Non-toxic doses of BOHB with oxaliplatin significantly amplified cytotoxicity in colorectal cancer organoids. Treatment with BOHB and/or melatonin resulted in significantly decreased lactate dehydrogenase A and increased mitochondrial carrier protein 2 levels, indicating inhibited aerobic glycolysis and an increased oxidative phosphorylation rate. This metabolic shift induced apoptotic cell death mediated by oxaliplatin, owing to high levels of ROS. Melatonin counteracted this effect by protecting cancer cells from high oxidative stress conditions. BOHB may enhance the efficacy of chemotherapeutics with a similar mechanism of action to oxaliplatin in colorectal cancer treatment. These innovative combinations could improve treatment outcomes for colorectal cancer patients.
细胞代谢失调最近已成为一个显著的癌症特征。这种关键代谢途径的重编程支持肿瘤生长。靶向癌症代谢显示出治疗结直肠癌的潜力。β-羟基丁酸（BOHB）作为三羧酸（TCA）循环的乙酰辅酶A来源，可能通过产生活性氧（ROS）将能量代谢途径导向TCA循环，从而增强对奥沙利铂的敏感性。本研究探讨了BOHB通过改变结直肠癌能量代谢来增强奥沙利铂细胞毒性作用的潜力。该研究采用了先进的体外类器官技术，成功模拟了体内生理学。通过细胞活力测定评估了BOHB和奥沙利铂的联合治疗效果。通过蛋白质免疫印迹分析了能量代谢、凋亡途径、DNA损伤标志物和组蛋白乙酰化相关关键蛋白的水平。通过流式细胞仪评估了ROS水平。无毒剂量的BOHB与奥沙利铂显著增强了结直肠癌类器官的细胞毒性。用BOHB和/或褪黑素处理导致乳酸脱氢酶A显著降低，线粒体载体蛋白2水平升高，表明有氧糖酵解受到抑制，氧化磷酸化速率增加。由于ROS水平较高，这种代谢转变诱导了奥沙利铂介导的凋亡细胞死亡。褪黑素通过保护癌细胞免受高氧化应激条件的影响来抵消这种作用。BOHB可能会增强与奥沙利铂作用机制相似的化疗药物在结直肠癌治疗中的疗效。这些创新组合可能会改善结直肠癌患者的治疗效果。
