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The inhibition of lactate dehydrogenase in cancer


Yudaitheska
(@yudaitheska)
Joined: 3 years ago
Posts: 32
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Lactate dehydrogenase (LDH) is an enzyme that catalyzes the interconversion of pyruvate-NADH and lactate-NAD+, critical for anaerobic respiration as it can recycle NAD+ for the continuation of glycolysis.

Human LDHA could be a molecular target for the inhibition of fermentative glycolysis and thus the growth and proliferation of cancer cells. Indeed, it is required for the initiation, maintenance, and progression of tumors. In addition, up-regulation of LDHA is characteristic of many cancer types,  and inhibition of LDHA by small molecules has been found to confer antiproliferative activity.  More importantly, complete deficiency of LDHA does not give rise to any symptoms in humans under normal circumstances,  indicating that selective LDHA inhibitors should only present minimal side effects.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086365

LDHA is elevated via the hypoxia inducible factor 1a and c-myc pathways.

Given this line of thought alpha linolenic acid would play a significant role since it stabilizes HIF-1a and downregulates Fasn. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642536/

Linolenic acid combined with another glycolisis inhibitor such as 2DG or high dose IV Vit C and oxamate would be a potent combination for inhibition of glycolysis. 


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Yudaitheska
(@yudaitheska)
Joined: 3 years ago
Posts: 32
Topic starter  

Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance

https://www.ncbi.nlm.nih.gov/m/pubmed/16766262/

Reduction in LDH-A activity resulted in stimulation of mitochondrial respiration and decrease of mitochondrial membrane potential. It also compromised the ability of these tumor cells to proliferate under hypoxia.


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Daniel
(@daniel)
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Joined: 6 years ago
Posts: 1058
 

@yudaitheska

Thanks Y. Indeed, we can expect that the inhibition of fermentation will lead to enhancement of respiration, and the other way around. This is why we want to inhibit both at the same time. If we inhibit fermentation only, it is still beneficial as tumours will develop slower. Here is a list of LDH inhibitors https://www.cancertreatmentsresearch.com/drugs-and-supplements-that-block-fermentation-and-help-fight-cancer/ Kind regards, Daniel


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