Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Type of study
Language
Publication year range
1.
Redox Biol ; 28: 101374, 2020 01.
Article in English | MEDLINE | ID: mdl-31743887

ABSTRACT

A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD+ ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity.


Subject(s)
Mitochondria/metabolism , Naphthoquinones/pharmacology , Oxidative Stress/drug effects , Oxygen Consumption/drug effects , Benzoquinones/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Doxorubicin/pharmacology , Glycolysis/drug effects , Humans , Lactams, Macrocyclic/pharmacology , Mitochondria/drug effects , Phenotype , Small Molecule Libraries/pharmacology , Vitamin K 3/pharmacology
2.
Hum Mol Genet ; 27(4): 577-588, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29228356

ABSTRACT

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with complex symptomology. In addition to a predisposition to tumors, children with NF1 can present with reduced muscle mass, global muscle weakness, and impaired motor skills, which can have a significant impact on quality of life. Genetic mouse models have shown a lipid storage disease phenotype may underlie muscle weakness in NF1. Herein we confirm that biopsy specimens from six individuals with NF1 similarly manifest features of a lipid storage myopathy, with marked accumulation of intramyocellular lipid, fibrosis, and mononuclear cell infiltrates. Intramyocellular lipid was also correlated with reductions in neurofibromin protein expression by western analysis. An RNASeq profile of Nf1null muscle from a muscle-specific Nf1 knockout mouse (Nf1MyoD-/-) revealed alterations in genes associated with glucose regulation and cell signaling. Comparison by lipid mass spectrometry demonstrated that Nf1null muscle specimens were enriched for long chain fatty acid (LCFA) containing neutral lipids, such as cholesterol esters and triacylglycerides, suggesting fundamentally impaired LCFA metabolism. The subsequent generation of a limb-specific Nf1 knockout mouse (Nf1Prx1-/-) recapitulated all observed features of human NF1 myopathy, including lipid storage, fibrosis, and muscle weakness. Collectively, these insights led to the evaluation of a dietary intervention of reduced LCFAs, and enrichment of medium-chain fatty acids (MCFAs) with L-carnitine. Following 8-weeks of dietary treatment, Nf1Prx1-/- mice showed a 45% increase in maximal grip strength, and a 71% reduction in intramyocellular lipid staining compared with littermates fed standard chow. These data link NF1 deficiency to fundamental shifts in muscle metabolism, and provide strong proof of principal that a dietary intervention can ameliorate symptoms.


Subject(s)
Muscular Diseases/diet therapy , Neurofibromatosis 1/diet therapy , Adolescent , Adult , Animals , Carnitine/therapeutic use , Child , Child, Preschool , Fatty Acids/therapeutic use , Female , Humans , Lipid Metabolism/physiology , Male , Mass Spectrometry , Mice , Mice, Knockout , Mice, Transgenic , Muscle Weakness/pathology , Muscle Weakness/therapy , Muscular Diseases/genetics , Muscular Diseases/pathology , Neurofibromatosis 1/genetics , Neurofibromatosis 1/pathology , Neurofibromin 1/genetics , Neurofibromin 1/metabolism , Quality of Life , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL
...