Drug Discovery
lyase99,100, fatty acid synthase101,102, monoglyc- eride lipase103,104 and carnitine palmitoyltrans- ferase 1C105). See 6,84,106 for more detailed reviews of some of these.
The final process within centralised metabolism is the export of end-point products/waste from the cell in order to protect the cell from build up of potentially toxic components and also to modify the extracellular vicinity around the cell which may act to assist the cell’s establishment in this environ- ment. In cancer cells the main exported substance from glucose metabolism is lactate which is effluxed via the transporter proteins MCT1 and MCT457,66. Studies have found MCT transporters
to be overexpressed in multiple tumour types107- 110 and that chemical or genetic inhibition of MCT function can reduce tumour growth suggesting that molecular targeted therapy against MCT trans- porters could be a possible mechanism for target- ing cancer metabolism57,111. Inhibitors targeting MCT1 have been successfully shown to affect in vitro and in vivo tumour growth and a MCT1 inhibitor designed by AstraZeneca (AZD-3965) is about to enter clinical trials as part of the CR:UK clinical development partnership. For glutamine metabolism it is believed ammonia released during the process of glutaminolysis diffuses into the extracellular environment by as yet undefined
Drug Discovery World Fall 2011
mechanisms. Understanding what these mecha- nisms could be may offer an attractive therapeutic strategy as inhibiting ammonia removal could cause build up of this toxic product and thereby potentially kill the tumour cell.
Therefore even in this stripped-down version of metabolism it is clear that tumours are adapting to maximise the usage of glucose and glutamine to promote survival and even growth in potential hos- tile environments and targeting these adaptions could be a therapeutic mechanism.
As understanding of cancer metabolism devel- ops, potential therapeutic targets are identified based on their roles in cancer metabolism coupled with cancer specific expression/isoforms, potential mutations and oncogenic control mechanisms. Targets which fit these profiles have been at the forefront of the new push for cancer metabolism drugs and examples include Pyruvate kinase M2 and Isocitrate dehydrogenase.
Pyruvate kinase M2 (PKM2) Pyruvate kinase (PK) catalyses the conversion of phosphoenolpyruvate (PEP) into pyruvate in a rate limiting and ATP generating step within glycolysis (Figure 3)2. There are multiple isoforms of PK of which the muscle form is of key interest in cancer cells89. PKM1 is found in muscle and brain and is
69
Figure 3 Oncogenic regulation of Pyruvate kinase M2 and ATP production. The active tetramer PK-M2 promotes glycolytic flux and ATP generation with a reduced output to other biosynthetic pathways. High ATP levels can have a negative feedback effect on this flux to reduce additional ATP generation (left panel). As a result of oncogenic driven phosphorylation, PK-M2 switches to the low activity dimeric form which results in less ATP production, a slowing of glycolytic flux and enhanced biosynthesis to meet the cancer cell biosynthetic demands. In cancer cells, pyruvate generation can also be uncoupled from ATP production by a novel mechanism by which phosphoenolpyruvate is converted to pyruvate by transference of a phosphate group to histidine-11 of phosphoglycerate mutase (PGAM1). This process also activates PGAM1 and so enhances flux at this point of glycolysis (right panel). Abbreviations: PGAM1 – phosphoglycerate mutase 1; ENO – enolase; PKM2 – pyruvate kinase M2; LDHa – lactate dehydrogenase-A; X? – Unknown phosphotransfer protein
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