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 jaspl akinolide, a cyclic depsipeptide from marine sponges, we examined whether j asplakinolide induces apoptosis in a variety of transformed and nontransfor med 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 wit h a fluorescent substrate, DEVD-MAC (N-acetyl-Asp-Clu-Yal-Asp-4-methyl-coum aryl-7-amide), the activity in the cells treated with jasplakinolide was re markably increased in a time-dependent manner. Pretreatment of Jurkat T cel ls with the caspase inhibitor zVAD [benzyloxycarbonyl(Cbz)-Val-Ala-beta -As p(OMe)-fluoromethyl ketone] or DEVD-CHO (N-acetyl-Asp-Clu-Val-Asp-1-aldehyd e) prevented the induction of apoptosis by jasplakinolide, Moreover, exposu re of various murine transformed cell lines to jasplakinolide resulted in c ell death, which was inhibited by zVAD. Although it has been well establish ed that murine immature thymocytes are sensitive to apoptosis when exposed to various apoptotic stimuli, these cells as well as mature T lymphocytes w ere resistant to jasplakinolide-induced apoptosis, The results suggest that jasplakinolide induces apoptotic cell death through a caspase-3-like prote ase-dependent pathway. Another important outcome is that transformed cell l ines were more susceptible to jasplakinolide-induced apoptosis than normal nontransformed cells.