Impaired mitochondrial respiration and stimulated glycolysis by m-iodobenzylguanidine (MIBG).
m-Iodobenzylguanidine (MIBG) is a functional analogue of the neurotransmitter norepinephrine. Radio-iodinated 131I-MIBG is used clinically as a tumor-targeted radiopharmaceutical agent in the diagnosis and treatment of adrenergic tumors. Native MIBG has previously been demonstrated to be cytotoxic in cultured cells and to produce anti-tumor responses in animals when non-toxic schedules are used. In this study the effect of MIBG was investigated on isolated rat liver mitochondria and on various tumor cell lines (human neuroblastoma SK-N-SH, mouse neuroblastoma N1E115 and mouse lymphosarcoma S49). Results revealed that MIBG inhibits respiration of isolated liver mitochondria at complex I of the respiratory chain, without affecting F1 ATP-ase. In cell lines, impairment of the mitochondrial respiration was evident from reduced oxygen consumption and decreased intracellular ATP levels. In response to this effect, the glycolytic flux was stimulated as shown by increased glucose consumption and lactic acid production. Cytotoxicity of MIBG was proportional to drug-induced alterations in glucose metabolism.
Loesberg
C
C
Department of Experimental Therapy, The Netherlands Cancer Institute/Antoni v. Leeuwenhoekhuis, Amsterdam.
Van Rooij
H
H
Nooijen
W J
WJ
Meijer
A J
AJ
Smets
L A
LA
D019797:3-Iodobenzylguanidine; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003287:Contrast Media / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007462:Iodobenzenes / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D003287:Contrast Media; D007462:Iodobenzenes; D019797:3-Iodobenzylguanidine; D000255:Adenosine Triphosphate; D005947:Glucose