Impairment of Aerobic Glycolysis by Inhibitors of Lactic Dehydrogenase Hinders the Growth of Human Hepatocellular Carcinoma Cell Lines

Fiume, L.; Manerba, Marcella; Vettraino, Marina; Stefano, Giuseppina Di

doi:10.1159/000317519

Cited by 51 publications

(36 citation statements)

References 36 publications

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“…When exposed to 40 mM (IC 50 value) of oxamate for 4 h, the production of lactic acid was reduced by 50%. The effective concentration of oxamate to suppress lactic acid production was similar to that previously reported (18,19). Hence, oxamate inhibits glycolysis in SGC-7901 cells.…”

Section: Morphological Changes In Gc Cells Treated With Oxamatesupporting

confidence: 87%

Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells

Liu

Yang

Chen³

et al. 2014

Oncology Reports

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Abstract. Lactate dehydrogenase A (LDH-A), which regulates glycolytic flux by catalyzing pyruvate to lactate in the cytoplasm, is believed to be one of the highly attractive therapeutic targets for cancers. Firstly, we detected the expression of LDH-A in gastric cancer (GC) cells. LDH-A inhibitor oxamate was then used to suppress the LDH-A activity in GC cells. Cell proliferation, lactic acid production, Transwell migration assay and apoptosis were assessed, respectively. The results showed that inhibition of LDH-A by oxamate decreased the lactate production. In the presence of glucose, oxamate inhibited cell proliferation in a dose-dependent manner. Flow cytometry assay further confirmed a pro-apoptotic effect of oxamate, and this was likely through increased expression of Bax, activated caspase-3, and decreased expression of Bcl-2. Therefore, we believe that oxamate inhibits cell growth, suppresses tumor invasion, and induces apoptosis in GC cells. LDH-A may be a potential therapeutic target for GC. IntroductionGastric cancer (GC) is one of the most common malignancies worldwide (1). Although the incidence has decreased in developed countries, it still remains an important public health burden in China (2). Globally, more than two-thirds of GC patients have unresectable disease at the time of diagnosis and 60% of resectable cases eventually relapse (3). The prognosis for advanced GC remains poor, with a 5-year survival rate of 26% (4). Therefore, more effective therapeutic approaches are urgently needed for GC patients.Altered metabolism is one of the critical hallmarks of cancers (5). Even in the presence of enough oxygen, tumor cells prefer to metabolize glucose by glycolysis rather than oxidative phosphorylation (6). In tumor cells, a substantial amount of pyruvate is reduced to lactate instead of being directed into the mitochondrion. Key alterations in metabolic pathways in tumor cells may create opportunities for the design of new anticancer approaches (7). In fact, agents targeting tumor metabolism have been proven useful in cancer therapy. In this aspect, traditional antimetabolites, such as methotrexate (MTX) and 5-fluorouracil (5-FU), have been used as chemotherapeutic agents for several decades (8). Most of these traditional antimetabolites target the final stages of the nucleotide synthesis and competitively inhibit the functioning of key enzymes involved in nucleic acid synthesis. However, these traditional anticancer agents only offer limited therapeutic benefits, and most of them are associated with severe adverse effects.Recent studies have indicated that deprivation of tumor cells of an energy supply can be a promising approach for cancer therapy. In mammalian cells, glucose is the key energy source for all tissues. Physiologically, glucose is converted to pyruvate via the glycolytic pathway, which is then either metabolized to lactic acid by lactic dehydrogenase (LDH) or enters the citric acid cycle in the matrix of the mitochondria (9). LDH-A is a cancer-specific isoform of LDH which convert...

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Section: Morphological Changes In Gc Cells Treated With Oxamatesupporting

confidence: 87%

Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells

Liu

Yang

Chen³

et al. 2014

Oncology Reports

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“…Reprogramming of metabolism is a hallmark of the oncogene-induced transformation. 20,[38][39][40][41] In tumors this oncogene-reprogramming can also influence the metabolism of the host microenvironment. 42 Warburg's pioneering studies have discovered in the glycolytic phenotype under aerobic conditions a dominant marker of neoplastic cells.…”

Section: Discussionmentioning

confidence: 99%

Transformation by different oncogenes relies on specific metabolic adaptations

et al. 2016

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Metabolic adaptations are emerging as common traits of cancer cells and tumor progression. In vitro transformation of NIH 3T3 cells allows the analysis of the metabolic changes triggered by a single oncogene. In this work, we have compared the metabolic changes induced by H-RAS and by the nuclear resident mutant of histone deacetylase 4 (HDAC4). RAS-transformed cells exhibit a dominant aerobic glycolytic phenotype characterized by up-regulation of glycolytic enzymes, reduced oxygen consumption and a defect in complex I activity. In this model of transformation, glycolysis is strictly required for sustaining the ATP levels and the robust cellular proliferation. By contrast, in HDAC4/TM transformed cells, glycolysis is only modestly up-regulated, lactate secretion is not augmented and, instead, mitochondrial oxygen consumption is increased. Our results demonstrate that cellular transformation can be accomplished through different metabolic adaptations and HDAC4/TM cells can represent a useful model to investigate oncogene-driven metabolic changes besides the Warburg effect.

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“…Unfortunately, radiation resistance always results in subsequent recurrence and metastasis of cancer, which leads to treatment failure. It has been reported that inhibition of LDH sensitizes cancer cells to chemotherapy (18)(19)(20). However, the relationship between LDH inhibition and radiosensitivity is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…A P-value <0.05 was considered to indicate a statistically significant result. confirm the LDH inhibition effect of oxamate as previously reported (18,19), a commercially available kit was used to determine the intracellular LDH enzyme activity after treatment with different doses of oxamate. The results showed that oxamate significantly decreased LDH activity (Fig.…”

Section: Assay Of Reactive Oxygen Species (Ros)mentioning

confidence: 97%

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Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells

et al. 2013

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Abstract. An elevated rate of glucose consumption and the dependency on aerobic glycolysis for ATP generation have long been observed in cancer cells, a phenomenon known as the Warburg effect. The altered energy metabolism in cancer cells provides an attractive opportunity for developing novel cancer therapeutic strategies. Lactate dehydrogenase (LDH), which catalyzes the transformation of pyruvate to lactate, plays a vital role in the process of glycolysis. It has been reported that the level of LDH-A expression is increased both in head and neck cancer cells and in the blood serum of nasopharyngeal carcinoma (NPC) patients, and is associated with poor prognosis. However, the effect of LDH-A inhibition on NPC cells remains unknown. Here, in the present study, we found that oxamate, a classical inhibitor of LDH-A, suppressed cell proliferation in a dose-and time-dependent manner both in CNE-1 and CNE-2 cells, two NPC cancer cell lines. LDH inhibition by oxamate induced G 2 /M cell cycle arrest via downregulation of the CDK1/cyclin B1 pathway and promoted apoptosis through enhancement of mitochondrial ROS generation. N-acetylcysteine, a specific scavenger of ROS, significantly blocked the growth inhibition effect induced by oxamate. We also identified that oxamate increased sensitivity to ionizing radiation in the two NPC cancer cell lines. Furthermore, we verified similar results in tumor xenograft models. Collectively, these results suggest that LDH-A may serve as a promising therapeutic target for NPC treatment.

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Impairment of Aerobic Glycolysis by Inhibitors of Lactic Dehydrogenase Hinders the Growth of Human Hepatocellular Carcinoma Cell Lines

Cited by 51 publications

References 36 publications

Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells

Effects of the suppression of lactate dehydrogenase A on the growth and invasion of human gastric cancer cells

Transformation by different oncogenes relies on specific metabolic adaptations

Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells

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