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Mitochondrial Metabolism Inhibitors for Cancer Therapy

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ABSTRACT

Cancer cells catabolise nutrients in a different way than healthy cells. Healthy cells mainly rely on oxidative phosphorylation, while cancer cells employ aerobic glycolysis. Glucose is the main nutrient catabolised by healthy cells, while cancer cells often depend on catabolism of both glucose and glutamine. A key organelle involved in this altered metabolism is mitochondria. Mitochondria coordinate the catabolism of glucose and glutamine across the cancer cell. Targeting mitochondrial metabolism in cancer cells has potential for the treatment of this disease. Perhaps the most promising target is the hexokinase-voltage dependent anion channel-adenine nucleotide translocase complex that spans the outer- and inner-mitochondrial membranes. This complex links glycolysis, oxidative phosphorylation and mitochondrial-mediated apoptosis in cancer cells. This review discusses cancer cell mitochondrial metabolism and the small molecule inhibitors of this metabolism that are in pre-clinical or clinical development.

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Abbreviations

alpha-TOS:

alpha-tocopheryl succinate

ANT:

adenine nucleotide translocase

ATP:

adenosine triphosphate

CAO:

4-(N-(S-cysteinylacetyl)amino) phenylarsonous acid

FADH2 :

flavin adenine dinucleotide

FH:

fumarate hydratase

GCAO:

4-(N-(S-cysteinylglycylacetyl)amino) phenylarsonous acid

G6P:

glucose-6-phosphate

GLUT:

glucose transporter

GPT:

glutamate pyruvate transaminase

GSAO:

4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid

HIF1:

hypoxia inducible factor 1

IDH:

isocitrate dehydrogenase

NADH:

nicotinamide adenine dinucleotide (reduced)

NADPH:

nicotinamide adenine dinucleotide phosphate (reduced)

NSCLC:

non-small-cell lung carcinoma

PENAO:

4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid

PDH:

pyruvate dehydrogenase

PDHK:

pyruvate dehydrogenase kinase

SDH:

succinate dehydrogenase

TCA:

tricarboxylic acid cycle

VDAC:

voltage dependent anion channel

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  1. Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, 2052, Australia

    Emma E. Ramsay, Philip J. Hogg & Pierre J. Dilda

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Pierre J. Dilda and Philip J. Hogg are co‐senior authors.

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Ramsay, E.E., Hogg, P.J. & Dilda, P.J. Mitochondrial Metabolism Inhibitors for Cancer Therapy. Pharm Res 28, 2731–2744 (2011). https://doi.org/10.1007/s11095-011-0584-5

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