title: Methadone induces necrotic-like cell death in SH-SY5Y cells by an impairment of mitochondrial ATP synthesis.
abstract: Methadone is a widely used therapeutic opioid in narcotic addiction and neuropathic pain syndromes. Oncologists regularly use methadone as a long-lasting analgesic. Recently it has also been proposed as a promising agent in leukemia therapy, especially when conventional therapies are not effective. Nevertheless, numerous reports indicate a negative impact on human cognition with chronic exposure to opiates. Thus, clarification of methadone toxicity is required. In SH-SY5Y cells we found that high concentrations of methadone were required to induce cell death. Methadone-induced cell death seems to be related to necrotic processes rather than typical apoptosis. Cell cultures challenged with methadone presented alterations in mitochondrial outer membrane permeability. A mechanism that involves Bax translocation to the mitochondria was observed, accompanied with cytochrome c release. Furthermore, no participation of known protein regulators of apoptosis such as Bcl-X(L) and p53 was observed. Interestingly, methadone-induced cell death took place by a caspases-independent pathway; perhaps due to its ability to induce a drastic depletion in cellular ATP levels. Therefore, we studied the effect of methadone on isolated rat liver mitochondria. We observed that methadone caused mitochondrial uncoupling, coinciding with the ionophoric properties of methadone, but did not cause swelling of the organelles. Overall, the effects observed for cells in the presence of supratherapeutic doses of methadone may result from a "bioenergetic crisis." A decreased level of cellular energy may predispose cells to necrotic-like cell death.
authors.affiliation: Neuropharmacology, Department of Medical Sciences, College of Medicine, University of Castilla-La Mancha (UCLM), Albacete, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Perez-Alvarez
authors.forename: Maria D
authors.initials: MD
authors.lastname: Cuenca-Lopez
authors.forename: Raquel M Melero-Fernández
authors.initials: RM
authors.lastname: de Mera
authors.forename: Elena
authors.initials: E
authors.lastname: Puerta
authors.forename: Andonis
authors.initials: A
authors.lastname: Karachitos
authors.forename: Piotr
authors.initials: P
authors.lastname: Bednarczyk
authors.forename: Hanna
authors.initials: H
authors.lastname: Kmita
authors.forename: Norberto
authors.initials: N
authors.lastname: Aguirre
authors.forename: Maria F
authors.initials: MF
authors.lastname: Galindo
authors.forename: Joaquin
authors.initials: J
authors.lastname: Jordán
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D042963:Electron Transport Complex II / Q000378:metabolism; D006801:Humans; D008691:Methadone / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C478189:respiratory complex II; D045304:Cytochromes c; D042963:Electron Transport Complex II; D020169:Caspases; D025261:Mitochondrial Proton-Translocating ATPases; D002118:Calcium; D008691:Methadone