RESUMO
The potential induction of a programmed cell death (PCD) in Trypanosoma b. brucei by 55 alkaloids of the quinoline, quinolizidine, isoquinoline, indole, terpene, tropane, steroid, and piperidine type was studied by measuring DNA fragmentation and changes in mitochondrial membrane potential. For comparison, the induction of apoptosis by the same alkaloids in human leukemia cells (Jurkat APO-S) was tested. Several alkaloids of the isoquinoline, quinoline, indole and steroidal type (berberine, chelerythrine, emetine, sanguinarine, quinine, ajmalicine, ergotamine, harmine, vinblastine, vincristine, colchicine, chaconine, demissidine and veratridine) induced programmed cell death, whereas quinolizidine, tropane, terpene and piperidine alkaloids were mostly inactive. Effective PCD induction (EC(50) below 10 microM) was caused in T. brucei by chelerythrine, emetine, sanguinarine, and chaconine. The active alkaloids can be characterized by their general property to inhibit protein biosynthesis, to intercalate DNA, to disturb membrane fluidity or to inhibit microtubule formation.
Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Fragmentação do DNA , Humanos , Substâncias Intercalantes , Células Jurkat , Fluidez de Membrana , Potencial da Membrana Mitocondrial , Microtúbulos , Biossíntese de Proteínas/efeitos dos fármacos , Tripanossomicidas/químicaRESUMO
The induction of apoptosis by 66 alkaloids of the quinoline, quinolizidine, pyrrolizidine, isoquinoline, indole, terpene, tropane, steroid, purine, and piperidine type, of 9 cardiac glycosides, 11 non-protein amino acids and 10 further secondary metabolites was assayed in HL-60 cell cultures and measured by quantification of the subdiploid DNA content by flow cytometry, detection of DNA fragmentation by gel electrophoresis, and cell morphology. Several alkaloids of the isoquinoline, quinoline, and indole type were active, whereas quinol-izidine, tropane, pyrrolizidine, terpene and piperdine alkaloids were mostly inactive. The proapoptotic alkaloids can be characterized by their property to inhibit protein biosynthesis and their intercalation into DNA at the same time, or by their inhibition of microtubule formation. All cardiac glycosides, which are both membrane detergents and Na+,K+-ATPase inhibitors, are potent apoptosis inducers. Also proapoptotic were a few non-protein amino acids, podophyllotoxin and the flavonoid quercetin.
Assuntos
Alcaloides/farmacologia , Aminoácidos/farmacologia , Apoptose/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Células HL-60/citologia , Morte Celular/efeitos dos fármacos , Fragmentação do DNA , DNA de Neoplasias/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HL-60/efeitos dos fármacos , Células HL-60/fisiologia , Humanos , Indóis/farmacologia , Isoquinolinas/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidoresRESUMO
Seven peptidyl proteasome inhibitors were tested for in vitro activity against Trypanosoma brucei bloodstream forms. Two compounds showed activity in the low nanomolar range. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of proteasome inhibitors for rational antitrypanosomal drug development.