Jasplakinolide induces apoptosis in various transformed cell lines by a caspase-3-like protease-dependent pathway.
To clarify the mechanisms underlying the antiproliferative effects of jasplakinolide, a cyclic depsipeptide from marine sponges, we examined whether jasplakinolide induces apoptosis in a variety of transformed and nontransformed cells. Jasplakinolide inhibited proliferation of human Jurkat T cells, resulting in cell death. This was accompanied by chromatin condensation and DNA cleavage at the linker regions between the nucleosomes. When caspase-3-like activity in the cytosolic extracts of Jurkat T cells was examined with a fluorescent substrate, DEVD-MAC (N-acetyl-Asp-Glu-Val-Asp-4-methyl-coumaryl-7-amide), the activity in the cells treated with jasplakinolide was remarkably increased in a time-dependent manner. Pretreatment of Jurkat T cells with the caspase inhibitor zVAD [benzyloxycarbonyl(Cbz)-Val-Ala-beta-Asp(OMe)-fluoromethylketone] or DEVD-CHO (N-acetyl-Asp-Glu-Val-Asp-1-aldehyde) prevented the induction of apoptosis by jasplakinolide. Moreover, exposure of various murine transformed cell lines to jasplakinolide resulted in cell death, which was inhibited by zVAD. Although it has been well established that murine immature thymocytes are sensitive to apoptosis when exposed to various apoptotic stimuli, these cells as well as mature T lymphocytes were resistant to jasplakinolide-induced apoptosis. The results suggest that jasplakinolide induces apoptotic cell death through a caspase-3-like protease-dependent pathway. Another important outcome is that transformed cell lines were more susceptible to jasplakinolide-induced apoptosis than normal nontransformed cells.
Odaka
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Department of Bacterial and Blood Products, National Institute of Infectious Diseases, Tokyo, Japan. odaka@nih.go.jp
Sanders
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Crews
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D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002461:Cell Line, Transformed; D003374:Coumarins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D047630:Depsipeptides; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D000590:Amino Acid Chloromethyl Ketones; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D047630:Depsipeptides; D009842:Oligopeptides; D010456:Peptides, Cyclic; C102580:acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin; C108637:aspartyl-glutamyl-valyl-aspartal; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C057531:jasplakinolide; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases