Recent Update on Human Lactate Dehydrogenase Enzyme 5 (<i>h</i>LDH5) Inhibitors: A Promising Approach for Cancer Chemotherapy

Rani, Reshma; Kumar, Vinit

doi:10.1021/acs.jmedchem.5b00168

Cited by 123 publications

(93 citation statements)

References 55 publications

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“…Gossypol, a natural phenol derived from cotton plants, inhibits LDHA by competing with NADH . Gossypol showed dose‐dependent cytotoxic activity in diverse cancer cells, including melanoma (SK‐mel‐19, SK‐mel‐28), small‐cell lung cancer (H69), breast cancer (Walker), cervical cancer (Sihas), myelogenous leukemia (K562), and glioma (HS683, U373, U87, and U138) .…”

Section: Ldha As a Biomarker And Therpeutic Target For Cancermentioning

confidence: 99%

“…Nevertheless, gossypol could interact with different cellular components involved in several biological functions, resulting in non‐specific toxicity of this compound. So further drug‐making attempts have produced frustrating results . Therefore, many gossypol analogs are being designed and under evaluation for their safety and anticancer efficacy.…”

Section: Ldha As a Biomarker And Therpeutic Target For Cancermentioning

confidence: 99%

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Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

et al. 2018

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Elevated glycolysis remains a universal and primary character of cancer metabolism, which deeply depends on dysregulated metabolic enzymes. Lactate dehydrogenase A (LDHA) facilitates glycolytic process by converting pyruvate to lactate. Numerous researches demonstrate LDHA has an aberrantly high expression in multiple cancers, which is associated with malignant progression. In this review, we summarized LDHA function in cancer research. First, we gave an introduction of structure, location, and basic function of LDHA. Following, we discussed the transcription and activation mode of LDHA. Further, we focused on the function of LDHA in cancer bio‐characteristics. Later, we discussed the clinical practice of LDHA in cancer prevention and treatment. What we discussed gives a precise insight into LDHA especially in cancer research, which will contribute to exploring cancer pathogenesis and its handling measures.

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Section: Ldha As a Biomarker And Therpeutic Target For Cancermentioning

confidence: 99%

Section: Ldha As a Biomarker And Therpeutic Target For Cancermentioning

confidence: 99%

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

et al. 2018

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“…This evidence shows LDH as a possible therapeutic anticancer target. Several different classes of inhibitor have been synthesized, such as the gossypol derivative FX-11, compound GNE-140, galloflavin, and others (61), although none of these molecules are under consideration in the clinic.…”

Section: Metabolic Pathways That Controls Emtmentioning

confidence: 99%

Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

et al. 2017

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The epithelial-to-mesenchymal transition (EMT) process allows the trans-differentiation of a cell with epithelial features into a cell with mesenchymal characteristics. This process has been reported to be a key priming event for tumor development and therefore EMT activation is now considered an established trait of malignancy. The transcriptional and epigenetic reprogramming that governs EMT has been extensively characterized and reviewed in the last decade. However, increasing evidence demonstrates a correlation between metabolic reprogramming and EMT execution. The aim of the current review is to gather the recent findings that illustrate this correlation to help deciphering whether metabolic changes are causative or just a bystander effect of EMT activation. The review is divided accordingly to the catabolic and anabolic pathways that characterize carbohydrate, aminoacid, and lipid metabolism. Moreover, at the end of each part, we have discussed a series of potential metabolic targets involved in EMT promotion and execution for which drugs are either available or that could be further investigated for therapeutic intervention.

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“…Various small molecules including natural as well as synthetic molecules exhibiting specific inhibitory activity against hLDH-5 have recently been identified and tested in preclinical studies [9,10]. The small molecule based drug discovery approach targeting hLDH-5 was further confirmed by the fact that suppression of hLDH-5 by small drugs could be utilized to kill cancer cells selectively, through apoptosis induction, irrespective of cancer cell p53 status and as a part of a combinatorial approach with redox-sensitive anticancer drugs via a novel p53/NAD(H)-dependent mechanism [11].…”

Section: Prospect For Potential Small Molecule Inhibitors Of Hldh-5 Ementioning

confidence: 99%

“…A large variety of small molecules showing selective hLDH5 inhibitory activity have been discovered and potent hLDH-5 inhibitors including GNE-140, FX11, galloflavin and RNAi have been studied preclinically as anticancer agents. Besides, several others hLDH-5 inhibitors such as gossypol (natural product), galloflavin, N-hydroxyindole derivatives, chimeric molecules and quinolone sulfonamide inhibitors have been developed [9]. However, none of these compounds were approved for clinical uses.…”

Section: Prospect For Potential Small Molecule Inhibitors Of Hldh-5 Ementioning

confidence: 99%

When Will Small Molecule Lactate Dehydrogenase Inhibitors Realize Their Potential in the Cancer Clinic?

Rani

Kumar

2017

Future Med. Chem.

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Keywords: cancer metabolism • drug discovery • hLDH5 inhibitors • tumor glycolysis • Warburg effectReaching beyond the success in development of anticancer drugs meant to precisely focus first on one hallmark of cancer and the production of a novel type of small molecules that are selective and specific for cancer treatment. Safety is a major challenge than the efficacy in the drug development processes of small molecules, for both the academic research and pharmaceutical industries. From a metabolic assessment, unlike normal cells, the most characteristic feature of cancer cells is an unusual metabolic profile exhibiting a high rate of glucose consumption and lactate production due to increased glycolytic activity to supply them sufficient energy and metabolites. This phenomenon, known as the 'Warburg effect' described the fact that the metabolic shift toward aerobic glycolysis is largely accepted as a key metabolic hallmark of cancer cells [1]. This metabolic alteration is independent of the availability of oxygen, resulting in increased levels of lactate and lower ATP production. Additionally, this metabolic trait provides a selective advantage for cancer cells to grow and proliferate and to support biomass synthesis even in the hypoxic environment. In fact, the 'glucose addiction' of cancer cells is considered to be an Achilles heel of cancer because of the highly susceptible nature of cancer cells to glucose withdrawal [2,3]. Is human lactate dehydrogenase-5 an innovative anticancer target?Recently, researchers from both academia and industries, have renewed interest in development of anticancer drugs by targeting human lactate dehydrogenase-5 (hLDH-5) and to explore the role of hLDH-5 in cancer initiation, growth and maintenance and its utility as a tumor biomarker. hLDH-5 enzyme occupies a crucial position in the Warburg effect and catalyzes the reduction of pyruvate coupled with the oxidation of nicotinamide adenine dinucleotide dehydrogenase (NADH) to form lactate and NAD (+) at the end in the final step of the glycolytic pathway. The NAD (+) thus obtained to determine the continuity of glycolysis [4]. Till date, the hLDH-5 isoform received a position in the list of highly promising hallmark of cancer, in other words, highly promising targets for cancer drug development and cancer treatment due to following main crucial facts such as: hLDH-5 isoform holds significant role as a metabolic checkpoint in the cancer glycolytic pathway; associations of this enzyme with the activation of some proto-oncogenes; its link with the maintenance of invasiveness and metastatic potential; and finally connection of hLDH-5 isoform to chemoresistance of cancer cells [5,6]. Is hLDH-5 a safe target?In our point of view, hLDH-5 isoform has significant functional roles in the development and survival of wide range of human cancers; thus, the total LDH activity and LDH isoform patterns could be utilized for diagnostic and prognostic significance and in neoplastic diseases. Kanno et al. found that the probable side effect mig...

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Recent Update on Human Lactate Dehydrogenase Enzyme 5 (hLDH5) Inhibitors: A Promising Approach for Cancer Chemotherapy

Cited by 123 publications

References 55 publications

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy

Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

When Will Small Molecule Lactate Dehydrogenase Inhibitors Realize Their Potential in the Cancer Clinic?

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