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Metabolism as a Therapeutic Target

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Unlike normal cells that oxidize pyruvate in the mitochondrial respiratory chain to produce bioenergy (ATP), tumors rely on a "fermentative", glycolytic metabolism that converts glucose to pyruvate and then lactate, irrespective of oxygen availability.

This metabolic reprogramming, known as "Warburg ...

Unlike normal cells that oxidize pyruvate in the mitochondrial respiratory chain to produce bioenergy (ATP), tumors rely on a "fermentative", glycolytic metabolism that converts glucose to pyruvate and then lactate, irrespective of oxygen availability.

This metabolic reprogramming, known as "Warburg effect", is now considered a distinct hallmark of cancer, although its relevance in cancer development appears to be even more general, as all the identified hallmarks rely on metabolic changes at some level. Indeed, decreased activity of Phase I enzymes, paralleled by enhancement of those of Phase II, is required for conferring resistance to ROS or chemically-induced toxicity; metabolic enzymes are required to initiate vessel sprouting during angiogenesis; modifications of the autophagic apparatus play a role either by eliminating defective organelles to reduce oxidative stress and prevent DNA damage or by enabling tumor cells to cope with their high metabolic demand. The fact that altered metabolism is not limited to energy metabolism reprogramming, but it is an essential feature of many other hallmarks has only recently been highlighted. Further support for metabolism involvement in cancer onset and development also comes from the identification of germline mutations in metabolic genes in patients affected by hereditary cancers.

Although the precise mechanisms responsible for the complex rewiring of metabolic circuitries remain poorly understood, it has recently become clear that they can be exploited as an Achilles’ heel for therapeutic targeting. Preclinical and clinical evidence, indeed, suggest that metabolism-targeting drugs can efficiently interfere with tumor progression. New strategies combining metabolic drugs with chemotherapy or targeted therapies are now under evaluation, with the hope that they can help to overcome resistance onset, at the moment, the main cause of therapeutic failure.

As this is a recent and rapidly evolving field, with several aspects not yet fully understood and often controversial, an overview of the obtained results and the future perspectives is highly desirable.


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