Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani 12120, Thailand.
Biomed Pharmacother. 2022 Jul;151:113214. doi: 10.1016/j.biopha.2022.113214. Epub 2022 May 28.
Three-dimensional (3D) cell culture models are used in cancer research because they mimic physiological responses in vivo compared with two-dimensional (2D) culture systems. Recently, cross-resistance of butyrate-resistant (BR) cells and chemoresistance in colorectal cancer (CRC) cells have been reported; however, effective treatments for BR cells have not been identified. In this study, we investigated the cytotoxicity of metformin (MET), an anti-diabetic drug, on BR CRC cells in a 3D spheroid culture model. The results demonstrate that MET decreases spheroid size, migration, and spheroid viability, while it increases spheroid death. The molecular mechanism revealed that AMP-activated protein kinase (AMPK) and Akt serine/threonine kinase 1(Akt) were significantly upregulated, whereas the acetyl-CoA-carboxylase (ACC) and mammalian target of rapamycin (mTOR) were downregulated, which led to caspase activation and apoptosis. Our findings show the potential cytotoxicity of MET on CRC-BR cells. The combination of MET and conventional chemotherapeutic drugs should be addressed in further studies to reduce the side effects of standard chemotherapy for CRC.
三维（3D）细胞培养模型用于癌症研究，因为它们与二维（2D）培养系统相比，更能模拟体内的生理反应。最近，已经报道了丁酸耐药（BR）细胞的交叉耐药性和结直肠癌（CRC）细胞的化疗耐药性；然而，尚未确定针对 BR 细胞的有效治疗方法。在这项研究中，我们在 3D 球体培养模型中研究了抗糖尿病药物二甲双胍（MET）对 BR CRC 细胞的细胞毒性。结果表明，MET 可减小球体大小、迁移和球体活力，同时增加球体死亡。分子机制表明，AMP 激活的蛋白激酶（AMPK）和 Akt 丝氨酸/苏氨酸激酶 1（Akt）显著上调，而乙酰辅酶 A 羧化酶（ACC）和雷帕霉素哺乳动物靶标（mTOR）下调，导致半胱天冬酶激活和细胞凋亡。我们的研究结果表明，MET 对 CRC-BR 细胞具有潜在的细胞毒性。应在进一步的研究中探讨 MET 与常规化疗药物的联合应用，以减少 CRC 标准化疗的副作用。
