Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism.
Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.
Gajate
Consuelo
C
Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
An
Feiyun
F
Mollinedo
Faustino
F
D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D005982:Glutathione Transferase / Q000378:metabolism; D018922:HL-60 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology*; D048670:MAP Kinase Kinase 4; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D000873:Anthracenes; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D047630:Depsipeptides; D010456:Peptides, Cyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; C432165:pyrazolanthrone; D045304:Cytochromes c; D005982:Glutathione Transferase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003474:Curcumin; C098980:plitidepsin