Lactic acid in cancer and mitochondrial disease

Abstract

Cancer and the mitochondrial diseases are disparate disorders that have in common a failure of normal cellular respiratory activity in disease-affected tissues. In mitochondrial diseases, the impairment in the mitochondria is often the result of abnormalities in their mtDNA, whereas in cancerous cells, the altered respiration is driven by the Warburg effect. The oxidation of glucose (as pyruvate in the mitochondria) is inhibited and energy production relies on cytoplasmic glycolysis. This suppressed mitochondrial activity confers in tumor cells a state of resistance to apoptosis and, in mitochondrial diseases like mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), the altered respiration leads to lactic acidosis. Driving glucose to its complete oxidation inside the mitochondria has potential in cancer therapy to reconstitute apoptotic competence in tumor cells and, in mitochondrial disease, to treat lactic acidosis. This minireview investigates the development of small molecule agents for suppressing the Warburg effect in cancer therapy and lactic acidosis in mitochondrial disease. Drug Dev Res 70 : 499-511, 2009.

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…Conversely, PMX-500FI localizes to the mitochondrial matrix using the body's carnitineacylcarnitine transport machinery [Steliou et al, 2009;El-Hattab and Scaglia, 2015]. There, it is recognized as a natural constituent and operated on in biochemical processes by mitochondrial enzymes [Steliou et al, 2009;Parameshwaran et al, 2010] that can amplify the short-lived anti-aging effects observed with AAM [Liu et al, 2002a,b;Shenk et al, 2009;Ames, 2010].…”

“…It has poor pharmacokinetic properties (short half-life and first-pass hepatic clearance) and multigram doses are needed to achieve therapeutic concentrations in vivo Moos et al, 2016]. However, when butyrate and other SCFAs, including lipoic acid, present as acylcarnitine esters [Knoop, 1904;Bieber et al, 1982;Bieber, 1988;Nałezcz et al, 2004;Houten and Wanders, 2010], the body's natural carnitine-acylcarnitine transport machinery actively delivers the ester into cells, an effect that substantially increases the bioavailability of the corresponding acyl-CoA [Chenault et al, 1988;Billhardt et al, 1989;Srinivas et al, 2007;Gong et al, 2008;Piermatti et al, 2008;Rosca et al, 2009;Steliou et al, 2009Steliou et al, , 2012Parameshwaran et al, 2010Parameshwaran et al, , 2012.…”

“…4), are actively transported and mitochondria-localizing biomimetic CoA surrogates of SCFAs [US Patents 6,316,652 and 8,741,853;Steliou et al, 2009Steliou et al, , 2012Steliou et al, , 2015Moos et al, 2016]. Mitochondria-targeting molecules attached to a triphenylphosphonium (TPP) cation also localize (by Coulombic pressure) in mitochondria, for example, the lipoic acid derivative, MitoL (Fig.…”

“…There, it is recognized as a natural constituent and operated on in biochemical processes by mitochondrial enzymes [Steliou et al, 2009;Parameshwaran et al, 2010] that can amplify the short-lived anti-aging effects observed with AAM [Liu et al, 2002a,b;Shenk et al, 2009;Ames, 2010].…”

D-Galactose Effectiveness in Modeling Aging and Therapeutic Antioxidant Treatment in Mice

“…12 In addition, we have synthesized a novel compound, PMX-500F, which is a lipoylcarnitine derivative. 13 In the current study, we tested whether chronic infusion of D-galactose would impair motor coordination, locomotor activity, and spatial reference memory. We also tested the effects of Lcarnitine, a-lipoic acid, and PMX-500F on control and Dgalactose-treated mice.…”