Development of novel human lactate dehydrogenase A inhibitors: High-throughput screening, synthesis, and biological evaluations

Zhou, Yuan; Tao, Pingde; Wang, Meigui; Xu, Peng; Lü, Wei; Pan, Lei; You, Qiuyun

doi:10.1016/j.ejmech.2019.05.033

Cited by 30 publications

(24 citation statements)

References 23 publications

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“…Additionally, the evaluation of the metabolic profile in MiaPaCa-2 cells treated by 24c exhibited a decreasing in ECAR and lactate production but an increased OCR value. Consequently, these observations suggested that 24c could be used as a lead pharmacophore for the development of new potent LDHA inhibitor (177).…”

Section: Therapeutic Approaches In Lactate Metabolismmentioning

confidence: 99%

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

et al. 2019

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Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as "Warburg effect or aerobic glycolysis." As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

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Section: Therapeutic Approaches In Lactate Metabolismmentioning

confidence: 99%

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

et al. 2019

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“…In the MiaPaCa-2 pancreatic carcinoma cell line, compound 24c resulted in dose-dependent reductions of cell growth and cell cycle arrest and apoptosis (Table 1). Furthermore, it suppressed tumor growth in a xenograft model [190]. These results suggest the use of compound 24c as a lead compound in the development of new, more potent LDHA inhibitors [190].…”

Section: Nonementioning

confidence: 85%

“…Furthermore, it suppressed tumor growth in a xenograft model [190]. These results suggest the use of compound 24c as a lead compound in the development of new, more potent LDHA inhibitors [190].…”

Section: Nonementioning

confidence: 85%

Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment

Pérez-Tomás

Pérez-Guillén

2020

Cancers

160

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Cancer is a complex disease that includes the reprogramming of metabolic pathways by malignant proliferating cells, including those affecting the tumor microenvironment (TME). The “TME concept” was introduced in recognition of the roles played by factors other than tumor cells in cancer progression. In response to the hypoxic or semi-hypoxic characteristic of the TME, cancer cells generate a large amount of lactate via the metabolism of glucose and glutamine. Export of this newly generated lactate by the tumor cells together with H+ prevents intracellular acidification but acidifies the TME. In recent years, the importance of lactate and acidosis in carcinogenesis has gained increasing attention, including the role of lactate as a tumor-promoting metabolite. Here we review the existing literature on lactate metabolism in tumor cells and the ability of extracellular lactate to direct the metabolic reprogramming of those cells. Studies demonstrating the roles of lactate in biological processes that drive or sustain carcinogenesis (tumor promotion, angiogenesis, metastasis and tumor resistance) and lactate’s role as an immunosuppressor that contributes to tumor evasion are also considered. Finally, we consider recent therapeutic efforts using available drugs directed at and interfering with lactate production and transport in cancer treatment.

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“…Tumors may be effectively treated by preventing the production of lactate and preventing its absorption. The anticancer compound 7ACC2 was found to be a potent MPC inhibitor that not only blocked the uptake of extracellular lactate continuously by promoting the accumulation of pyruvate in the cell and preventing glucose oxidative metabolism but also improved the sensitivity of transplanted tumors to radiation therapy [ 67 ]. The significance of lactate in tumorigenesis, progression, and treatment resistance suggests that inhibiting lactate production and blocking lactate sources may be a viable approach for treating cancer.…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment: Lactic Acid Promotes Tumor Development

Gao

Zhou

Liu

et al. 2022

Journal of Immunology Research

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Lactic acid is a “metabolic waste” product of glycolysis that is produced in the body. However, the role of lactic acid in the development of human malignancies has gained increasing interest lately as a multifunctional small molecule chemical. There is evidence that tumor cells may create a large amount of lactic acid through glycolysis even when they have abundant oxygen. Tumor tissues have a higher quantity of lactic acid than normal tissues. Lactic acid is required for tumor development. Lactate is an immunomodulatory chemical that affects both innate and adaptive immune cells’ effector functions. In immune cells, the lactate signaling pathway may potentially serve as a link between metabolism and immunity. Lactate homeostasis is significantly disrupted in the TME. Lactate accumulation results in acidosis, angiogenesis, immunosuppression, and tumor cell proliferation and survival, all of which are deleterious to health. Thus, augmenting anticancer immune responses by lactate metabolism inhibition may modify lactate levels in the tumor microenvironment. This review will evaluate the role of lactic acid in tumor formation, metastasis, prognosis, treatment, and histone modification. Our findings will be of considerable interest to readers, particularly those engaged in the therapeutic treatment of cancer patients. Treatments targeting the inhibition of lactate synthesis and blocking the source of lactate have emerged as a potential new therapeutic option for oncology patients. Additionally, lactic acid levels in the plasma may serve as biomarkers for disease stage and may be beneficial for evaluating therapy effectiveness in individuals with tumors.

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Development of novel human lactate dehydrogenase A inhibitors: High-throughput screening, synthesis, and biological evaluations

Cited by 30 publications

References 23 publications

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment

Tumor Microenvironment: Lactic Acid Promotes Tumor Development

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