Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics

IF 12.1 1区医学 Q1 ONCOLOGY Seminars in cancer biology Pub Date : 2022-12-01 DOI:10.1016/j.semcancer.2022.11.007

Dolly Sharma , Mamta Singh , Reshma Rani

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引用次数: 26

Abstract

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.

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LDH在肿瘤糖酵解中的作用:小分子调控LDHA用于癌症治疗

乳酸脱氢酶(乳酸脱氢酶)是有氧糖酵解的关键酶之一，它催化糖酵解的最后一步，即丙酮酸转化为乳酸。大多数癌细胞的特点是肿瘤糖酵解速率提高，以确保快速生长的癌细胞的能量需求，从而增加乳酸的产生。过量的乳酸产生细胞外酸中毒，促进侵袭、血管生成和转移，并影响免疫反应。癌细胞内乳酸穿梭和乳酸共生关系的建立，可能进一步增加不良预后。一些遗传和表型研究确定了乳酸脱氢酶A (LDHA)或LDH5(亚基A的一个同质四聚体)在癌症发生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。到目前为止，已经发现了几种具有显著的LDHA抑制活性和抗癌活性的小分子，因此，通过LDHA抑制靶向肿瘤糖酵解而提高选择性来饥饿癌细胞可以产生替代的抗癌治疗方法。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。本综述还旨在提供具有抗癌特性的重要LDHA抑制剂的最新进展和该领域的未来发展方向。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Seminars in cancer biology 医学-肿瘤学

CiteScore

26.80

自引率

4.10%

发文量

347

审稿时长

15.1 weeks

期刊介绍： Seminars in Cancer Biology (YSCBI) is a specialized review journal that focuses on the field of molecular oncology. Its primary objective is to keep scientists up-to-date with the latest developments in this field. The journal adopts a thematic approach, dedicating each issue to an important topic of interest to cancer biologists. These topics cover a range of research areas, including the underlying genetic and molecular causes of cellular transformation and cancer, as well as the molecular basis of potential therapies. To ensure the highest quality and expertise, every issue is supervised by a guest editor or editors who are internationally recognized experts in the respective field. Each issue features approximately eight to twelve authoritative invited reviews that cover various aspects of the chosen subject area. The ultimate goal of each issue of YSCBI is to offer a cohesive, easily comprehensible, and engaging overview of the selected topic. The journal strives to provide scientists with a coordinated and lively examination of the latest developments in the field of molecular oncology.