Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency

Maekawa, Masato; Sudo, Kayoko; Kanno, Takashi; Li, Steven S.‐L.

doi:10.1016/0006-291x(90)92374-9

Cited by 54 publications

(22 citation statements)

References 16 publications

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“…Germline mutations in LDHA have been reported demonstrating loss of LDHA protein expression associated only with mild exertional myopathy, highlighting the potential therapeutic window of specific LDHA inhibitors. 16,17 Ongoing drug development efforts have been devoted to the identification of increasingly specific LDHA inhibitors, and our findings support efforts to evaluate the preclinical efficacy of novel LDHA antagonists in both MYCN -amplified and MYCN -single copy neuroblastomas.…”

Section: Discussionsupporting

confidence: 63%

FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells

Rellinger

Craig

Alvarez

et al. 2017

Surgery

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Background The MYC family promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. Methods We surveyed three MYCN-single copy and five MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis. Results LDHA is frequently expressed in both MYCN-amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN-single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis. Conclusions Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas.

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Section: Discussionsupporting

confidence: 63%

FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells

Rellinger

Craig

Alvarez

et al. 2017

Surgery

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“…LDHA is generally considered a safe therapeutic target in humans because an inherited 20-bp deletion in the LDHA gene, which results in the loss of LDHA protein, has only relatively mild symptoms of exertional myopathy (48,49). Accordingly, several LDHA inhibitors are being tested for their anticancer activity (Table 1).…”

Section: Ldha Inhibitors As Cancer Therapeuticsmentioning

confidence: 99%

Targeting lactate metabolism for cancer therapeutics

Doherty¹,

Cleveland²

2013

J. Clin. Invest.

894

876

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Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.

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“…Case by case differences in disease severity were noted. DNAanalysis of a family with consanguinity revealed 20 base pair (bp) deletion of the sixth exon of LDH-A (4,5). Wereport the genetic analysis of severe cases that had no history of consanguinity through four generations.…”

Section: Introductionmentioning

confidence: 99%

Genetic Analysis of a Family of Lactate Dehydrogenase A Subunit Deficiency.

1995

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Lactate dehydrogenase A subunit (LDH-A) deficiency is an inherited metabolic myopathy of glycolysis. The severity of this disease varies from case to case. Wereported non-consanguineous male sibling cases whohad severe muscle pain and rhabdomyolysis during anaerobic exercise. Genetic analysis revealed 20 base pair deletion of the sixth exon of the LDH-Agene. There was no difference in the gene abnormality between our patients and previously reported female cases who had history of consanguinity and lower degree of symptoms. The differences in disease severity were not due to genomic abnormality in our two families. (Internal Medicine 34: 326-329, 1995)

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Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency

Cited by 54 publications

References 16 publications

FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells

FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells

Targeting lactate metabolism for cancer therapeutics

Genetic Analysis of a Family of Lactate Dehydrogenase A Subunit Deficiency.

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