LDH inhibition impacts on heat shock response and induces senescence of hepatocellular carcinoma cells

Manerba, Marcella; Ianni, Lorenza Di; Govoni, Marzia; Roberti, Marinella; Recanatini, Maurizio; Stefano, Giuseppina Di

doi:10.1016/j.ejps.2017.05.015

Cited by 26 publications

(16 citation statements)

References 48 publications

(61 reference statements)

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“…Strategies to overcome these challenges include development of novel delivery methods for LDHi, or combinatorial approaches that might allow for lower doses of LDHi to be effective. Based on published data, kinase inhibitors, HSP90 inhibitors, oxidative phosphorylation inhibitors, and inducers of reactive oxygen species represent several potential combination partners worthy of further study (5,(44)(45)(46)(47). In conclusion, our findings suggest that further translational preclinical work is necessary to optimize the potential of LDHi as anticancer agents, but that due to their exquisite sensitivity to glycolytic impairment, Ewing sarcoma may be one of the best indications for their use.…”

Section: Discussionmentioning

confidence: 76%

Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma

et al. 2019

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Altered cellular metabolism, including an increased dependence on aerobic glycolysis, is a hallmark of cancer. Despite the fact that this observation was first made nearly a century ago, effective therapeutic targeting of glycolysis in cancer has remained elusive. One potentially promising approach involves targeting the glycolytic enzyme lactate dehydrogenase (LDH), which is overexpressed and plays a critical role in several cancers. Here, we used a novel class of LDH inhibitors to demonstrate, for the first time, that Ewing sarcoma cells are exquisitely sensitive to inhibition of LDH. EWS-FLI1, the oncogenic driver of Ewing sarcoma, regulated LDH A (LDHA) expression. Genetic depletion of LDHA inhibited proliferation of Ewing sarcoma cells and induced apoptosis, phenocopying pharmacologic inhibition of LDH. LDH inhibitors affected Ewing sarcoma cell viability both in vitro and in vivo by reducing glycolysis. Intravenous administration of LDH inhibitors resulted in the greatest intratumoral drug accumulation, inducing tumor cell death and reducing tumor growth. The major dose-limiting toxicity observed was hemolysis, indicating that a narrow therapeutic window exists for these compounds. Taken together, these data suggest that targeting glycolysis through inhibition of LDH should be further investigated as a potential therapeutic approach for cancers such as Ewing sarcoma that exhibit oncogene-dependent expression of LDH and increased glycolysis.Significance: LDHA is a pharmacologically tractable EWS-FLI1 transcriptional target that regulates the glycolytic dependence of Ewing sarcoma.

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Section: Discussionmentioning

confidence: 76%

Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma

et al. 2019

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“…In order to set the connection between HSR and LDH, an inhibitor of the LDH activity (Oxamate) by direct competition with its natural substrate was used in a hepatocellular carcinoma (HCC) derived cell model. Oxamate, was found to impact the constitutively activated HSR by reducing the levels of the HSP-27,−72, and−90 (181). Additionally, Galloflavin, hindered the ATPase activity of HSP 72 and 90, both compounds resulted in cell senescence.…”

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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“…Real Time-PCR was performed by following the procedure already described in [ 14 ]. Cells were seeded at a density of 2 x 10 4 /cm 2 and allowed to adhere overnight.…”

Section: Methodsmentioning

confidence: 99%

“…It was performed as previously described in [ 14 ]. MCF-10A cells were plated into 6-well plates, at the density of 250 cells/well, in triplicate.…”

Section: Methodsmentioning

confidence: 99%

The activation of lactate dehydrogenase induced by mTOR drives neoplastic change in breast epithelial cells

et al. 2018

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mTOR kinase and the A isoform of lactate dehydrogenase (LDH-A) are key players controlling the metabolic characteristics of cancer cells. By using cultured human breast cells as a “metabolic tumor” model, we attempted to explore the correlation between these two factors. “Metabolic tumors” are defined as neoplastic conditions frequently associated with features of the metabolic syndrome, such as hyper-insulinemia and hyper-glycemia. MCF-7 cells (a well differentiated carcinoma) and MCF-10A cells (a widely used model for studying normal breast cell transformation) were used in this study. These cells were exposed to known factors triggering mTOR activation. In both treated cultures, we evaluated the link between mTOR kinase activity and the level of LDH expression / function. Furthermore, we elaborated the metabolic changes produced in cells by the mTOR-directed LDH-A up-regulation. Interestingly, we observed that in the non-neoplastic MCF-10A culture, mTOR-directed up-regulation of LDH-A was followed by a reprogramming of cell metabolism, which showed an increased dependence on glycolysis rather than on oxidative reactions. As a consequence, lactate production appeared to be enhanced and cells began to display increased self-renewal and clonogenic power: signals suggestive of neoplastic change. Enhanced clonogenicity of cells was abolished by rapamycin treatment, and furthermore heavily reduced by LDH enzymatic inhibition. These results highlighted a mechanistic link between metabolic alterations and tumorigenesis, whereby suggesting LDH inhibition as a possible chemo-preventive measure to target the metabolic alterations driving neoplastic change.

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LDH inhibition impacts on heat shock response and induces senescence of hepatocellular carcinoma cells

Cited by 26 publications

References 48 publications

Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma

Targeting Glycolysis through Inhibition of Lactate Dehydrogenase Impairs Tumor Growth in Preclinical Models of Ewing Sarcoma

Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

The activation of lactate dehydrogenase induced by mTOR drives neoplastic change in breast epithelial cells

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