title: Cytotoxicity of dopamine-derived tetrahydroisoquinolines on melanoma cells.
abstract: Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds detected in urine, central nervous system and some peripheral tissues in Mammalia. No data are at present available on TIQ levels in skin, although in vitro biochemical evidences indicate that they may undergo auto-oxidation with production of reactive oxygen species or may be enzymatically converted into melanin pigments. The effect of two catechol-bearing TIQs, salsolinol (SAL) and tetrahydropapaveroline (THP), on the viability of melanotic or amelanotic melanoma cell lines was investigated. Both SAL and THP were well tolerated up to roughly 30 microM and became overtly toxic at higher concentrations, with SAL being better tolerated than THP. Intracellular activity of some antioxidant enzymes, tyrosinase and alpha-ketoglutarate dehydrogenase was also evaluated to assess the cell response to oxidative and metabolic challenge of TIQs treatment. Catalase and superoxide dismutase pre-treatment only partially prevented TIQs toxicity while a complete protection was obtained with N-acetylcysteine and GSH. TIQs were able to provoke upregulation of the scavenging enzymes catalase and DT-diaphorase and to determine a decrease of the alpha-ketoglutarate dehydrogenase activity. SAL and THP enhanced tyrosinase activity and melanin production, suggesting that they were indeed tyrosinase substrates leading to melanin formation. The results support the evidence that TIQs were toxic toward melanoma cells, leading to their death by necrosis. TIQs toxicity was likely due to increased oxidative stress by generation of reactive oxygen species and oxidative metabolites. Our study represents an intent to furnish an additional contribution for the comprehension of catechol cytotoxicity.
authors.affiliation: Laboratory of Virology, Regina Elena Institute for Cancer Research, Via delle Messi d'Oro, 156-00156 Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: De Marco
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Marcante
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.forename: Cesira
authors.initials: C
authors.lastname: Foppoli
authors.forename: Carla
authors.initials: C
authors.lastname: Blarzino
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: Rosei
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000737:chemistry*; D004347:Drug Interactions; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008545:Melanoma / Q000473:pathology*; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D007546:Isoquinolines; D009498:Neurotoxins; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D014442:Monophenol Monooxygenase; D007655:Ketoglutarate Dehydrogenase Complex; D004298:Dopamine