Cancer cells undergo a significant level of “metabolic reprogramming” or “remodeling” to ensure an adequate supply of ATP and “building blocks” for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure–activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy.
癌细胞经历显著的“代谢重编程”或“重塑”，以确保充足的ATP供应和细胞生存所需的“构建模块”，并促进加速增殖。癌细胞优先利用糖酵解产生ATP（瓦博格效应）；然而，包括结直肠癌（CRC）细胞在内的癌细胞也依赖氧化磷酸化（OXPHOS）产生ATP，这一发现表明糖酵解和OXPHOS在促进癌症进展和增殖中均发挥重要作用。我们先前的研究发现了一种半合成异黄酮类化合物DBI-1，可作为靶向线粒体复合物I的AMPK激活剂。此外，DBI-1与葡萄糖转运蛋白1（GLUT1）抑制剂BAY-876在体外和体内协同抑制CRC细胞生长。现我们报告一项针对异黄酮类化合物家族构效关系（SARs）的研究，其中我们鉴定出一种新的DBI-1类似物，即DBI-2，具有良好特性。本研究旨在探索DBIs的抗肿瘤机制，并通过同时靶向糖酵解和OXPHOS开发新的联合策略。我们通过AMPK磷酸化检测确定DBI-2为一种新型AMPK激活剂。在海马实验分析中，DBI-2抑制线粒体复合物I。我们进行了增殖和蛋白质印迹实验，并对细胞凋亡、坏死和自噬进行研究，以证实DBI-2与BAY-876在体外对CRC细胞的协同作用。我们假设通过生酮饮食（KD）限制碳水化合物摄入可模拟GLUT1抑制剂的效果，并发现生酮饮食显著增强了DBI-2在CRC异种移植小鼠模型中的治疗效果，这一结果为联合癌症治疗提供了一种潜在新策略。
肿瘤(癌症)患者之家