Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Graduate Program of Physiology and Integrative Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Oncogene. 2021 Mar;40(12):2285-2295. doi: 10.1038/s41388-021-01688-7. Epub 2021 Mar 1.
Pancreatic ductal adenocarcinoma (PDA) is aggressive cancer characterized by rapid progression, metastatic recurrence, and highly resistant to treatment. PDA cells exhibit aerobic glycolysis, or the Warburg effect, which reduces the flux of pyruvate into mitochondria. As a result, more glycolytic metabolites are shunted to pathways for the production of building blocks (e.g., ribose) and reducing agents (e.g., NADPH) for biosynthesis that are necessary for cell proliferation. In addition, PDA cells are highly addicted to glutamine for both maintaining biosynthetic pathways and achieving redox balance. Mitochondrial uncoupling facilitates proton influx across the mitochondrial inner membrane without generating ATP, leading to a futile cycle that consumes glucose metabolites and glutamine. We synthesized a new mitochondrial uncoupler MB1-47 and tested its effect on cancer cell metabolism and the anticancer activity in pancreatic cancer cell models and murine tumor transplantation models. MB1-47 uncouples mitochondria in the pancreatic cancer cells, resulting in: (1) the acceleration of pyruvate oxidation and TCA turnover; (2) increases in AMP/ATP and ADP/AMP ratios; and (3) a decrease in the synthesis rate of nucleotides and sugar nucleotides. Moreover, MB1-47 arrests cell cycle at G-G phase, reduces clonogenicity, and inhibits cell growth of murine and human pancreatic cancer cells. In vivo studies showed that MB1-47 inhibits tumor growth in murine tumor transplantation models, and inhibits the hepatic metastasis when tumor cells were transplanted intrasplenically. Our results provide proof of concept for a potentially new strategy of treating PDA, and a novel prototype experimental drug for future studies and development.
胰腺导管腺癌 (PDA) 是一种侵袭性癌症，其特征为快速进展、转移性复发和对治疗具有高度抗性。PDA 细胞表现出有氧糖酵解，即瓦博格效应，这会减少丙酮酸进入线粒体的通量。结果，更多的糖酵解代谢物被分流到用于构建块（例如核糖）和还原剂（例如 NADPH）的生物合成途径，这些是细胞增殖所必需的。此外，PDA 细胞对谷氨酰胺高度依赖，这既是为了维持生物合成途径，也是为了实现氧化还原平衡。线粒体解偶联促进质子穿过线粒体内膜流入，而不产生 ATP，导致葡萄糖代谢物和谷氨酰胺被消耗的无效循环。我们合成了一种新的线粒体解偶联剂 MB1-47，并在胰腺癌细胞模型和小鼠肿瘤移植模型中测试了其对癌细胞代谢和抗癌活性的影响。MB1-47 使胰腺癌细胞中的线粒体解偶联，导致：(1) 加速丙酮酸氧化和 TCA 周转；(2) 增加 AMP/ATP 和 ADP/AMP 比值；(3) 核苷酸和糖核苷酸的合成速率降低。此外，MB1-47 使细胞周期停滞在 G1-G0 期，降低集落形成能力，并抑制小鼠和人胰腺癌细胞的生长。体内研究表明，MB1-47 抑制小鼠肿瘤移植模型中的肿瘤生长，并抑制肿瘤细胞脾内移植时的肝转移。我们的结果为治疗 PDA 的潜在新策略提供了概念验证，并为未来的研究和开发提供了一种新的原型实验药物。
