Anti-apoptotic and apoptotic action of (-)-deprenyl and its metabolites.
The mode of cytoprotective action of the monoamine oxydase B inhibitor (-)-deprenyl was studied using A-2058 human melanoma cells in culture. Serum deprivation caused apoptosis of the cultured cells, which could be decreased by administration of 10(-9) - 10(-13)M (-)-deprenyl. The known metabolites of (-)-deprenyl, (-)-desmethyl-deprenyl, (-)- and (+)-methylamphetamine failed to exert the same effect. The anti-apoptotic activity of (-)-deprenyl was prevented by the simultaneous application of the microsomal drug-metabolizing enzyme inhibitor SKF-525A. These results show that (-)-deprenyl needs metabolic conversion in order to be anti-apoptotic, but the effective metabolite is still unknown. On the other hand, higher dose (10(-13)M) of (-)-deprenyl, (-)-desmethyl-deprenyl, (-)- and (+)-methylamphetamine induced apoptosis in the non-serum-deprived A-2058 cell culture. SKF-525A did not prevent the apoptosis-inducing effect of (-)-deprenyl, which means that no metabolic changes are needed for this activity. High dose (10(-3)M) of (-)-deprenyl induced very high Caspase 3 activity in non-serum-deprived A-2058 cell culture, low doses (10(-9) - 10(-3) M) of (-)-deprenyl maintained Caspase 3 activity on control level in case of serum-deprivation.
Szende
B
B
1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. bszende@korb1.sote.hu
Bökönyi
G
G
Bocsi
J
J
Kéri
G
G
Timár
F
F
Magyar
K
K
D018663:Adrenergic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008545:Melanoma; D008694:Methamphetamine / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011335:Proadifen / Q000494:pharmacology; D012642:Selegiline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D018663:Adrenergic Agents; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D012642:Selegiline; D008694:Methamphetamine; D011335:Proadifen; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases