Peloruside A enhances apoptosis in H-ras-transformed cells and is cytotoxic to proliferating T cells

Peloruside A (peloruside), a compound isolated from the marine sponge Mycale hentscheli, inhibits growth of human (HL-60) and mouse (32D-ras) myeloid leukemic cells, as well as non-transformed 32D cells. Using the MTT cell proliferation assay and trypan blue dye exclusion tests, little difference was seen in growth inhibition between 32D and 32D-ras cells; however, peloruside was more cytotoxic to the oncogene-transformed cells. Peloruside also blocked 32D-ras cells more readily in G(2)/M of the cell cycle, leading to apoptosis. Annexin-V/propidium iodide staining of 32D and 32D-ras cells showed that 1.6 muM peloruside induced significant cell death by 36 hours in 32D cells (16% survival), but to comparable levels as early as 14 hours in 32D-ras cells (11% survival). There was no evidence for activation of either of the initiator caspases-8 or -9 by 0.1 muM peloruside following 12 hours of exposure. Peloruside inhibited T cell proliferation and IL-2 and IFNgamma production in both the mixed lymphocyte reaction and following CD3 cross-linking, and this effect was shown to be a non-specific cytotoxic effect. It is concluded that peloruside preferentially targets oncogene-transformed cells over non-transformed cells by inducing transformed cells to undergo apoptosis.