Fig. 5.

Efficiency of targeting lactate/H+ symporters for anticancer therapy. a Few oxidative cancer cells could use lactate to generate ATP, thus inhibition of monocarboxylate transporter 1 (MCT1) with AstraZeneca’s specific inhibitor AZD3965 results in growth arrest. Other type of cancer cells, glycolytic and expressing only MCT1, will be also sensitive to MCT1 inhibitor showing growth reduction, cell death and radiosensitivity. b Most of glycolytic cancer cells are expressing both MCT1 and MCT4. Due to functional redundancy between these two MCTs, AZD3965 will have no effect on hypoxic regions of the tumours. c Combined inhibition of MCT1 and MCT4 results in decreased glycolytic rate and severe growth arrest. However, increased intracellular lactic acid pool and subsequently increased intracellular pyruvate concentration, will fuel the tricarboxylic (TCA) cycle leading to metabolic shift from glycolysis towards OXPHOS. Therefore, tumour cells, although growing slowly, will survive by keeping physiological ATP pool and escape lactate export blockade. d Concomitant application of MCT inhibitors with metformin or phenformin, which inhibits OXPHOS, induces synthetic lethality resulting in “ATP crisis”. Consequently, rapid tumour cell death occurs due to “metabolic catastrophe.” Basigin (BSG); MCT4 inhibitor (MCT4 i)