Key Points
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The metabolism observed in tumours is different from that of the normal tissues from which the tumours are derived. This altered metabolic phenotype allows cancer cells to accommodate increased metabolic demands and adapt to environmental changes.
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Specific alterations in metabolic pathways may generate opportunities to design new therapeutic approaches.
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Metabolic alterations in cancer can be driven by changes in signalling pathways involving kinases such as PI3K and mTOR, and transcription factors, including hypoxia inducible factor and MYC. These are important targets for cancer therapy in general and cancer metabolism in particular.
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Cancer cells increase their rate of glucose and glutamine metabolism for bioenergetic and anabolic purposes. These important external carbon sources are diverted to generate DNA, proteins and lipids that are required for cancer cell growth.
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Cancer-specific isoforms of enzymes involved in energy metabolism, anabolism and adaptation to low oxygen may be new druggable targets for cancer therapy with potentially improved therapeutic indices compared with current therapy.
Abstract
Cancer therapy has long relied on the rapid proliferation of tumour cells for effective treatment. However, the lack of specificity in this approach often leads to undesirable side effects. Many reports have described various 'metabolic transformation' events that enable cancer cells to survive, suggesting that metabolic pathways might be good targets. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways of tumours. This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
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We would like to thank C. Frezza, J. Swinnen and S. Mazurek for their input and advice on the manuscript.
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Glossary
- Glycolysis
-
The pathway leading from intracellular glucose directly to pyruvate, resulting in the generation of two moles of pyruvate, ATP and NADH from one mole of glucose.
- Glutaminolysis
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The process by which glutamine is metabolised to α-ketoglutarate by glutamate.
- Pentose phosphate pathway
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A bypass of glycolysis with both biosynthetic and antioxidant outcomes. It can generate NADPH and/or ribose-5-phosphate, which can be used for glutathione reduction and anabolic processes.
- Tricarboxylic acid cycle
-
A set of interconnected pathways in the mitochondrial matrix. It produces reducing equivalents (NADH and FADH2) for the electron transport chain and precursors for amino acid and fatty acid synthesis.
- Pasteur effect
-
First used to describe the inhibitory effect of oxygen on yeast fermentation. It is now described as the inhibition of glycolysis by mitochondria-generated ATP that is observed in eukaryotic cells.
- Warburg effect
-
Originally described as the large increase in aerobic production of lactate by cancer cells and suggested to be a consequence of defects in oxidative phosphorylation. Today, it is defined as an increase in 'aerobic glycolysis' that is not necessarily correlated with permanent mitochondrial dysfunction.
- Anapleurosis
-
From the Greek 'ana' meaning 'up' and 'plerotikos' meaning 'to fill', this term describes the replenishment of TCA cycle intermediates.
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Tennant, D., Durán, R. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10, 267–277 (2010). https://doi.org/10.1038/nrc2817
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DOI: https://doi.org/10.1038/nrc2817
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