Lonidamine cytotoxicity: Involvement of the lysosomal compartment

Lonidamine (LND) was found to decrease significantly the pH gradient across intracellular compartments in Ehrlich ascites tumour cells. The effect was maximal in the range 0.2 - 0.3 mM LND, and was observed both in the presence of glucose - i.e. conditions in which a high bioenergetic status of the cells was maintained by glycolysis (due to a strong Crabtree effect in these cells) - and in the absence of glucose. Moreover the LND effect was also observed in the presence of bafilomycin, a specific inhibitor of the H+-vacuolar ATPase. Based on these findings, we suggest that the LND effect on the proton gradient reflects an LND-induced increase in membrane proton conductance. The consequent impairment of intracellular proton gradients might be involved in the mechanism of action of LND, allowing drugs that are weak bases to accumulate preferentially in the cytoplasm and nucleus.