The potential of lactate and succinate to kill nutrient deprived tumor cells by intracellular acidification

We have investigated the ability of the weak acids, lactate, succinate, and the monomethylester of succinate, to cause intracellular acidification of EMT-6 and MGH-U1 cells. Each of the three substances caused a decrease of intracellular pH (pHi) when the cell lines were exposed at low extracellular pH (pHe) in the range 6.0-6.5. Only monomethylsuccinate caused intracellular acidification at neutral pHe. The fall in pHi increased with increasing dose of each agent and with decreasing pHe. The pHi recovered to almost normal values after exposure of 30 minutes to 50 mM lactate, but there was little or no recovery of pHi in the presence of succinate or monomethylsuccinate. Succinate and its methylester were toxic to cells at low pHe (less than 6.5), and cell killing increased with exposure time and with dose of the agents used. Lactate did not cause cell death at low pHe, and none of the three substances exhibited any cytotoxicity at neutral pHe. Solid tumors are known to have an acidic microenvironment, and pHe may be particularly low in regions of hypoxia. Succinate and its monomethylester may have the potential to kill cells in acidic regions of tumors and might therefore enhance the effect of radiation.