Drug Discovery Opinion

Tumours are heterogeneous and contain both oxygenated and hypoxic regions. Cells in regions with low oxygen levels mainly use glucose for glycolytic energy production and release lactic acid in the process. It had been thought that tumour cells with an ample oxygen supply primarily used glucose for oxidative energy production, but a new study published in the Journal of Clinical Investigation shows that lactate plays a major role in fuelling the oxidative metabolism of these cells. Cells in different regions of a tumour are thus able to mutually regulate their access to energy metabolites, reserving glucose for use by cells in hypoxic regions and recycling their waste product. The study also identified the monocarboxylate transporter 1 (MCT1) as the main route of lactate uptake and, using three different tumour models, showed that blocking MCT1 with α-cyano-4-hydroxycinnamate or siRNA caused a switch from lactate-fuelled respiration to glycolysis. This switch in metabolism of oxygenated cells induces necrosis of distant hypoxic cells by effectively starving them of glucose. These hypoxic cells are known to be very aggressive and difficult to kill with conventional treatments. The reduced oxygen consumption by surviving tumour cells after MCT1 inhibition also rendered the tumours more sensitive to the effects of radiotherapy.

Since MCT1 is expressed in a variety of primary human tumours, the study demonstrates the therapeutic potential of MCT1 inhibitors, as well as the likely benefit of combining these with radiotherapy.

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