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Melanoma cell death induced by sphingosine and betulinic acid [Abstract]
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Background: Melanoma cells are known to be especially resistant, in vitro, to induction of apoptotic cell death by classical chemotherapeutic agents; this correlates with the negligible clinical efficacy of these agents against melanoma. However, 2 classes of chemotherapeutic agents, betulinic acid and sphingolipids, have recently demonstrated activity against melanoma cells. Results: Betulinic acid selectively kills neuroectodermal neoplastic cells, primarily melanoma and neuroblastoma cells, through apoptotic pathways. We have confirmed by 5 separate assay methods that betulinic acid kills human SK23 melanoma cells by inducing apoptosis. However, selectivity for neuroectodermal cells is not universal, since the myelomonocytic cell line, HL60, was equally sensitive to this drag. Further studies of the in vitro toxicity of betulinic acid may lead to clinical applications for this drug. Sphingolipids are known to inhibit cellular proliferation, and sphingosine in particular has been shown to induce apoptosis in various cell types. We show that sphingosine kills SK23 cells by apoptosis at exposures greater than 20 hours. In contrast, sphingosine kills HL60 cells by apparently nonapoptotic mechanisms within 0.5 to 1 hours, and pretreatment for 24 hours with dihydroxy-vitamin D[Symbol Not Transcribed] greatly enhances this toxicity. This suggests induction by this fat-soluble vitamin of a metabolic pathway involved in the mediation of sphingosine toxicity. This rapid sphingosine-induced nonapoptotic cell kill in HL60 cells may represent a novel mechanism of cell death inducible by dihydroxy-vitamin D[Symbol Not Transcribed]. Conclusion: Elucidating the mechanisms of apoptotic and nonapoptotic cell death and the pathways of sphingosine metabolism in different cell lines may lead to novel chemotherapeutic approaches to melanoma.