Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Future Med Chem. 2020 Mar;12(5):439-455. doi: 10.4155/fmc-2019-0287. Epub 2020 Feb 17.
Dysregulated metabolism is one of the hallmarks of cancer. Under normal physiological conditions, ATP is primarily generated by oxidative phosphorylation. Cancers commonly undergo a dramatic shift toward glycolysis, despite the presence of oxygen. This phenomenon is known as the Warburg effect, and requires the activity of LDHA. LDHA converts pyruvate to lactate in the final step of glycolysis and is often upregulated in cancer. LDHA inhibitors present a promising therapeutic option, as LDHA blockade leads to apoptosis in cancer cells. Despite this, existing LDHA inhibitors have shown limited clinical efficacy. Here, we review recent progress in LDHA structure, function and regulation as well as strategies to target this critical enzyme.
代谢失调是癌症的特征之一。在正常生理条件下，ATP 主要通过氧化磷酸化产生。尽管存在氧气，癌症通常会急剧转向糖酵解。这种现象称为瓦博格效应，需要 LDHA 的活性。LDHA 在糖酵解的最后一步将丙酮酸转化为乳酸，并且在癌症中经常上调。LDHA 抑制剂提供了一种有前途的治疗选择，因为 LDHA 阻断导致癌细胞凋亡。尽管如此，现有的 LDHA 抑制剂显示出有限的临床疗效。在这里，我们回顾了 LDHA 的结构、功能和调节方面的最新进展，以及针对这种关键酶的策略。
