Meta-iodobenzylguanidine (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 structural analogue of norepinephrine, on SK-N-BE(2c) cells. In micromolar concentrations, MIBG caused almost complete inhibition of the proliferation of SK-N-BE(2c) cells. In intact SK-N-BE(2c) cells, addition of MIBG 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 increasing concentrations of MIBG. In cells treated with digitonin, MIBG inhibited malate driven ATP synthesis. Comparable inhibition of ATP synthesis with succinate as a substrate required higher concentrations of MIBG. These results indicate that, apart from inhibition of complex I, MIBG was capable of inhibiting at least one other complex of the respiratory chain. Although maximal inhibition of ATP synthesis was observed at a concentration of 10 microM, optimal inhibition of cell proliferation occurred at a MIBG concentration > 25 microM. This suggests that MIBG also influences other cellular processes apart from mitochondrial ATP synthesis, resulting in additional inhibition of cell proliferation.
Cornelissen
J
J
Department of Pediatrics and Clinical Chemistry, University of Amsterdam, The Netherlands.
Wanders
R J
RJ
Van den Bogert
C
C
Van Kuilenburg
A B
AB
Elzinga
L
L
Voûte
P A
PA
Van Gennip
A H
AH
D019797:3-Iodobenzylguanidine; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007462:Iodobenzenes / Q000494:pharmacology*; D008293:Malates / Q000037:antagonists & inhibitors; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D013386:Succinates / Q000037:antagonists & inhibitors; D019802:Succinic Acid; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007462:Iodobenzenes; D008293:Malates; D013386:Succinates; D019797:3-Iodobenzylguanidine; C030298:malic acid; D000255:Adenosine Triphosphate; D019802:Succinic Acid