METAIODOBENZYLGUANIDINE (MIBG) INHIBITS MALATE AND SUCCINATE DRIVEN MITOCHONDRIAL ATP SYNTHESIS IN THE HUMAN NEUROBLASTOMA CELL-LINE SK-N-BE(2C)

In this paper, we report on our studies of the effects of MIBG, a stru ctural analogue of norepinephrine, on SK-NB-E(2c) cells. In micromolar concentrations, MIBG caused almost complete inhibition of the prolife ration of SKN-BE(2c) cells. In intact SK-N-BE(2c) cells, addition of M IBG led to a decrease of the ATP to ADP ratio. A progressive increase of the lactate to pyruvate ratio (due to increased lactate production) was observed after incubation of the cells with glucose and increasin g concentrations of MIBG. In cells treated with digitonin, MIBG inhibi ted malate driven ATP synthesis. Comparable inhibition of ATP synthesi s with succinate as a substrate required higher concentrations of MIBG . These results indicate that, apart from inhibition of complex I, MIB G was capable of inhibiting at least one other complex of the respirat ory chain. Although maximal inhibition of ATP synthesis was observed a t a concentration of 10 mu M, optimal inhibition of cell proliferation occurred at a MIBG concentration > 25 mu M. This suggests that MIBG a lso influences other cellular processes apart from mitochondrial ATP s ynthesis, resulting in additional inhibition of cell proliferation.