(2017) Myotoxicity of statins: mechanism of action. Pharmacol. respiration, ATP-linked respiration, and ATP creation. LOV and SIM didn’t change the rate of lactic acid production. In summary, statins modulate mitochondrial metabolism in cancer cells independently of the Chol content in cellular membranes without affecting glycolysis.Christie, C. F., Fang, D., Hunt, E. G., Morris, M. E., Rovini, A., Heslop, K. A., Beeson, G. C., Beeson, C. C., Maldonado, E. N. Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content. cholesterol (Chol) synthesis in the mevalonate pathway (1, 2). In spite of the effectiveness in decreasing plasmatic Chol, 20% of the population who have a clinical indication for statin therapy display intolerance to these drugs (3). The most common adverse effects are myopathies, which include myalgia, muscle stiffness and tenderness, loss of muscle strength, and cramps (4). In rare cases, damage to muscles progresses to fatal rhabdomyolysis (5C7). Although some evidence suggests that mitochondrial dysfunction might be the cause of statin-induced myopathies, the molecular mechanisms remain undetermined (8). Statins have also been proposed to decrease cancer progression. Several meta-analyses have associated statins with a reduced risk of developing liver, prostate, gastric, lung, esophageal, and colorectal cancers, although a beneficial effect on tumor development is still controversial (9). Statins increased survival in patients with hepatocellular carcinoma and simple squamous cell carcinoma of the head, neck, and cervix by a median of 9 and 7.5 mo, respectively (10, 11). Statins arrested choroidal melanoma, lung cancer, hepatocellular carcinoma, and breast cancer cells in the G1 phase of the cell cycle and induced apoptosis (12C14). Statins also induced mitochondrial dysfunction and apoptosis in all-trans retinoic acid-resistant promyelocytic leukemia (15). The metabolic consequences of statins on tumor cells are poorly understood. A distinctive feature of cancer cells is the Warburg phenotype characterized by enhanced glycolysis and partial suppression of mitochondrial metabolism (16). The current consensus is that the Warburg phenotype favors proliferation by providing carbon backbones for the synthesis of biomass (lipids, proteins, and nucleic acids) required for the formation of new cells. Tumor mitochondria contribute to cell bioenergetics by generating ATP and also metabolic intermediaries for the biosynthetic needs of proliferating cells (17, 18). Total cellular ATP generation is contributed both by mitochondrial oxidative phosphorylation (oxphos) and glycolysis. Oxphos generates more than 95% of ATP in nonproliferating cells, whereas in cancer cells, aerobic glycolysis accounts for 20C90% of ATP formation (19, 20). Respiratory substrates (fatty acyl-CoAs, pyruvate, and certain amino acids), ADP, and inorganic phosphate (Pi) enter the mitochondrial matrix Leptomycin B after crossing the mitochondrial outer and inner membranes. Respiratory substrates fuel the Krebs cycle to generate reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are oxidized by the electron transport chain. The Leptomycin B electron transport chain pumps protons into the intermembrane space at complexes I, III, and IV to produce a proton motive force further used by the ATP F1-F0 synthase to generate ATP from STEP ADP and Pi. The higher concentration of protons in the intermembrane space relative to that of the matrix form the negative mitochondrial membrane potential (), a useful readout to follow changes in mitochondrial metabolism in intact cells (21C24). The relative contribution of oxphos and glycolysis, genetically determined, vary substantially over time depending on multiple nongenetic factors. Availability of different fuels, level of oxygenation, Leptomycin B stage of the cell cycle, proximity to newly formed mature blood vessels, and pharmacological manipulation influence the oxidative or glycolytic phenotype. In many tumors, a decrease in mitochondrial metabolism triggers an increase in the Warburg phenotype and (25C27). In preliminary studies, short-term treatment with lovastatin (LOV) ( 6 h) in human liver hepatocellular carcinoma cell line HepG2 cells increased without changes in cell morphology, whereas longer treatments (72C96 h) collapsed and promoted cell shrinking among other morphologic changes. It has been shown that although simvastatin (SIM) inhibits HMG-CoA reductase in HepG2 cells, total Chol content remains unchanged after 18C24 h of treatment (28, 29). The loss of cellular morphology after 72C96 h of LOV is consistent with a decrease in Chol content, which is essential for the maintenance of the structure of cellular membranes. Chol content has been reported to decrease after exposing HepG2 and human prostate cancer (C4-2) cells to statins for more than 48 h (30, 31). The short-term LOV-dependent increase in in cancer cells led to the hypothesis that statins promote mitochondrial hyperpolarization.

(2017) Myotoxicity of statins: mechanism of action