Increased lactate production follows loss of mitochondrial membrane potential during apoptosis of human leukaemia cells

Acute tumour-lysis syndrome (ATLS) is a frequently fatal complication after cytoreductive leukaemia therapy. Lactic acidosis is associated with ATLS a nd its extent is correlated with the severity of ATLS. In the course of cyt oreductive therapy, apoptosis is Induced in tumour cells, which results in loss of mitochondrial function. We hypothesize that loss of mitochondrial f unction leads to compensatory glycolysis, which is the main cause of lactat e accumulation and acidosis. We tested this hypothesis using the model of g lucocorticoid-induced apoptosis in the human acute lymphoblastic leukaemia cell line CCRF-CEM. After induction of glucocorticoid-induced apoptosis, a biphasic course of lactate production was observed. Prior to the onset of a poptosis, i.e. prior to the loss of membrane potential, lactate production was reduced. However, subsequent to loss of mitochondrial membrane potentia l a massive increase in lactate production was observed (15.5 +/- 0.5 versu s10.17 +/- 0.09 mmol/10(6) cells, P = 0.001). We also demonstrated that inh ibition of respiratory chain activity by antimycin A resulted in excess lac tate production. In the model cell line used, conditional bcl-2 expression delayed glucocorticoid-induced apoptosis by protecting against loss of mito chondrial membrane potential; bcl-2 expression delayed the increase in lact ate production and had no effect on the pre-apoptotic drop in lactate produ ction. Apoptosis-induced lactate production was also observed in other cell lines (HL60, THP1 and OPM2) with various cytotoxic agents [doxorubicin, ge mcitabine and vumon (VM26)]. Thus, the data suggest that lactate acidosis c an be caused by apoptotic loss of mitochondrial function and massive apopto sis of a tumour mass via lactic acidosis may be the essential pathological event in ATLS.