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.

Abstract

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.

• Authors: Elaine Maria Souza-Fagundes, Gabriela Brumatti, Olindo Assis Martins-Filho, Rodrigo Corrêa-Oliveira, Carlos Leomar Zani, Gustavo Pessini Amarante-Mendes
• Journal: Experimental cell research (Exp Cell Res) Vol. 290 Issue 2 Pg. 420-6 (Nov 01 2003) ISSN: 0014-4827 [Print] United States
• PMID: 14567999 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Diterpenes
• Enzyme Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Tumor Necrosis Factor
• Receptors, Tumor Necrosis Factor, Type I
• fas Receptor
• Cytochromes c
• CASP3 protein, human
• CASP8 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 8
• Caspase 9
• Caspases

Topics

• Antigens, CD (metabolism)
• Apoptosis (drug effects)
• Asteraceae (chemistry)
• Blotting, Western
• Caspase 3
• Caspase 8
• Caspase 9
• Caspases (metabolism)
• Cell Cycle
• Cytochromes c (metabolism)
• Diterpenes (isolation & purification, pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Humans
• Jurkat Cells (drug effects, enzymology)
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, enzymology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Tumor Necrosis Factor (metabolism)
• Receptors, Tumor Necrosis Factor, Type I
• Signal Transduction (drug effects)
• fas Receptor (metabolism)