Myriadenolide, a labdane diterpene isolated from Alomia myriadenia (asteraceae) induces depolarization of mitochondrial membranes and apoptosis associated with activation of caspases-8, -9, and -3 in Jurkat and THP-1 cells.
Myriadenolide is a diterpene that we have recently isolated from the extract of Alomia myriadenia (Asteraceae). Here we show for the first time that myriadenolide has caspase-dependent cytotoxic activity against human leukemia cells from both lymphocytic (Jurkat) and monocytic (THP-1) lineages, because preincubation of Jurkat or THP-1 cells with the broad-spectrum caspase inhibitor z-VAD-fmk completely abrogated cell death. Moreover, the mitochondrial pathway is implicated as mitochondrial depolarization and caspase-9 and caspase-3 activation were observed. Interestingly, caspase-8 and cleavage of the proapoptotic member of the Bcl-2 family BID was also observed during apoptosis induced by myriadenolide, suggesting a role for the caspase-8/BID pathway. However, interference with Fas or TNFR1 signaling did not interfere with apoptosis in our experimental system. Furthermore, pretreatment of cells with the caspase-3 inhibitor DEVD-fmk completely blocked the activation of caspase-8, suggesting that the activation of the caspase-8/BID pathway is part of an amplification loop initiated by caspase-3. Taken together, our results indicate myriadenolide as a novel candidate for the treatment of hematological malignancies.
Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, MG, Brazil.
Elaine Maria
EM
Souza-Fagundes
Gabriela
G
Brumatti
Olindo Assis
OA
Martins-Filho
Rodrigo
R
Corrêa-Oliveira
Carlos Leomar
CL
Zani
Gustavo Pessini
GP
Amarante-Mendes
D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D019659:Asteraceae / Q000737:chemistry*; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle; D045304:Cytochromes c / Q000378:metabolism; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
D015703:Antigens, CD; D004224:Diterpenes; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor; D045304:Cytochromes c; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases