Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics
Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics
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DOI：
10.1016/j.semcancer.2022.11.007
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发表时间：
2022-11-22
影响因子：
14.5
通讯作者：
Rani, Reshma
中科院分区：
文献类型：
--
作者：
Sharma, Dolly;Singh, Mamta;Rani, Reshma
乳酸脱氢酶（LDH）是有氧糖酵解中的关键酶之一，催化糖酵解的最后一步，即丙酮酸转化为乳酸。大多数癌细胞的特征在于肿瘤糖酵解速率增强，以确保快速生长的癌细胞的能量需求，从而导致乳酸盐产量增加。过量的乳酸产生细胞外酸中毒，其促进侵袭、血管生成和转移并影响免疫应答。乳酸穿梭和乳酸共生在癌细胞中建立，这可能进一步增加不良预后。几项遗传和表型研究确定了乳酸脱氢酶A（LDHA）或LDH 5（A亚基的一种同源四聚体）在癌症发展和转移中的潜在作用。LDHA被认为是药物设计和发现的可行靶标。迄今已发现几种小分子表现出显著的LDHA抑制活性和抗癌活性，因此，通过具有改善的选择性的LDHA抑制靶向肿瘤糖酵解来饥饿癌细胞可以产生替代的抗癌治疗剂。本文综述了LDHA在代谢重编程中的作用及其与原癌基因和癌基因的关系。本次审查的目的还在于提供一个重要的LDHA抑制剂的抗癌特性和未来的发展方向在这一领域的更新。
Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most cancer cells are characterized by an enhanced rate of tumor glycolysis to ensure the energy demand of fast-growing cancer cells leading to increased lactate production. Excess lactate creates extracellular acidosis which facilitates invasion, angiogenesis, and metastasis and affects the immune response. Lactate shuttle and lactate symbiosis is established in cancer cells, which may further increase the poor prognosis. Several genetic and phenotypic studies established the potential role of lactate dehydrogenase A (LDHA) or LDH5, the one homo-tetramer of subunit A, in cancer development and metastasis. The LDHA is considered a viable target for drug design and discovery. Several small molecules have been discovered to date exhibiting significant LDHA inhibitory activities and anticancer activities, therefore the starvation of cancer cells by targeting tumor glycolysis through LDHA inhibition with improved selectivity can generate alternative anticancer therapeutics. This review provides an overview of the role of LDHA in metabolic reprogramming and its association with proto-oncogenes and oncogenes. This review also aims to deliver an update on significant LDHA inhibitors with anticancer properties and future direction in this area.