Induction of apoptosis by the marine sponge (Mycale) metabolites, mycalamide A and pateamine

The marine sponge metabolites mycalamide A (myca-lamide) and pateamine are extremely cytotoxic. While mycalamide has been shown to inhibit protein syn thesis, the mechanism by which these compounds induce cell death is unknown . Using DNA laddering, Annexin-V staining, and morphological analysis, we d emonstrate that both metabolites induce apoptosis in several different cell lines. Furthermore, both mycalamide and pateamine were more potent inducer s of apoptosis in the 32D myeloid cell line after transformation with eithe r the ras or bcr-abl oncogenes. This increased sensitivity was also observe d in response to the protein synthesis inhibitors cycloheximide and puromyc in, and cytosine-beta -D-arabinofurano-side (Ara-C), an inducer of DNA dama ge. We propose, therefore, that in 32D cells where Ras signalling has been altered either by constitutive expression of oncogenic ras or by Bcr/abl-me diated perturbation of upstream signalling events, increased susceptibility to apoptosis by a range of stimuli is conferred.