title: Antiproliferative and depigmenting effects of the histamine (H2) agonist dimaprit and its derivatives on human melanoma cells.
abstract: Human melanoma cells were treated in culture with the histamine (H2) agonist S-(3-(N-N-dimethylamino)propyl)isothiourea (dimaprit), a partial agonist, S-(2-(N,N-dimethylamino)ethyl)-isothiourea (nordimaprit), and two analogues of nordimaprit, S-(2-(N,N-diethylamino)ethyl)isothiourea (DENOR) and S-(2-(N,N-diisopropylamino)ethyl)isothiourea (DINOR), to investigate the effects on toxicity and tyrosinase activity. Cell survival studies showed highest toxicity in the constitutively pigmented human melanoma cell line MM418, DINOR being the most effective agent. Toxicity was not blocked by the H2 antagonist cimetidine. Dimaprit and its derivatives decreased tyrosinase activity in the amelanotic human melanoma cell line MM96E and inhibited expression of a melanosomal antigen. Loss of tyrosinase activity could be prevented by cimetidine and ranitidine, an H2 antagonist. Although the tyrosinase activity in MM418 cells was much more resistant to inhibition by these agents compared with that in MM96E cells, prolonged growth in the presence of non-toxic levels of DINOR caused a decrease in tyrosinase activity and subsequent depigmentation. Ultrastructural examination of the depigmented cells showed a decrease in the number of melanized melanosomes and the appearance of premelanosomes. These results indicate that bulky substituents on the tertiary amine group in nordimaprit significantly enhance potency for depigmentation and cell killing but only the former effect is mediated by the H2 receptor.
authors.affiliation: Pharmacy Department, University of Queensland.
authors.forename: G A
authors.initials: GA
authors.lastname: Fechner
authors.forename: P G
authors.initials: PG
authors.lastname: Parsons
authors.forename: M T
authors.initials: MT
authors.lastname: McEwan
authors.forename: J J
authors.initials: JJ
authors.lastname: Jacobs
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D002927:Cimetidine / Q000494:pharmacology; D017259:Dimaprit / Q000031:analogs & derivatives; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000378:metabolism; D008854:Microscopy, Electron; D014442:Monophenol Monooxygenase / Q000032:analysis / Q000037:antagonists & inhibitors; D010858:Pigmentation / Q000187:drug effects; D011899:Ranitidine / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D011970:Receptors, Histamine H2; C025838:nordimaprit; D002927:Cimetidine; D011899:Ranitidine; D014442:Monophenol Monooxygenase; D013890:Thiourea; D017259:Dimaprit