title: Release mechanisms of [125I]meta-iodobenzylguanidine in neuroblastoma cells: evidence of a carrier-mediated efflux.
abstract: [131I]metaiodobenzylguanidine ([131I]MIBG) is selectively taken up and stored by tumours derived from the neural crest, and is used for diagnosis and treatment of neuroblastoma (NB). The antitumoral effect of [131I]MIBG is closely related to the intracellular level of the radiopharmaceutical compound, which is dependent on uptake and storage/release mechanisms. While MIBG uptake is well characterised, storage and release mechanisms are still controversial. In order to better characterise [125I]MIBG release mechanisms, we studied the basal and stimulated efflux of [125I]MIBG in the human NB cell line, SH-SY5Y, preloaded with 0.1 microM [125I]MIBG for 1 h. We found that [125I]MIBG basal efflux is highly temperature-dependent, that [125I]MIBG release, induced by cell depolarisation with high potassium, is mainly calcium-independent, and induced by exchange with cold MIBG or noradrenaline, inversion of the sodium gradient across the cell membrane by veratridine by substitution of sodium chloride with equimolar concentration of lithium chloride. The exposure of NB cells to imipramine, an Uptake-1 inhibitor, also produces a net stimulatory effect on [125I]MIBG release. However, when used in association with other releasing stimuli, such as higher levels of intracellular sodium or external agonists, imipramine abolishes the consequent increase of [125I]MIBG release. Our findings suggest that stimulated [125I]MIBG release is mediated by a carrier, most probably the uptake carrier working in a reverse mode, while a minimal fraction of [125I]MIBG is released by an exocytotic mechanism.
authors.affiliation: Division of Pediatric Oncology, Catholic University, Rome, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Servidei
authors.forename: A
authors.initials: A
authors.lastname: Iavarone
authors.forename: A
authors.initials: A
authors.lastname: Lasorella
authors.forename: S
authors.initials: S
authors.lastname: Mastrangelo
authors.forename: R
authors.initials: R
authors.lastname: Riccardi
mesh_terms: D019797:3-Iodobenzylguanidine; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D007462:Iodobenzenes / Q000493:pharmacokinetics*; D009447:Neuroblastoma / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D013696:Temperature; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D007462:Iodobenzenes; D019797:3-Iodobenzylguanidine; D007099:Imipramine; D011188:Potassium