Cytotoxic effects of sphingolipids as single or multi-modality agents on human melanoma and soft tissue sarcoma in vitro.
We evaluated the cytotoxic effects of a cell-permeable ceramide (Cer), N-hexanoyl-D-sphingosine (C6-Cer) and of two related sphingoid bases, sphingosine (So) and dihydrosphingosine (sphinganine; Sa) on human melanoma cell lines and on soft tissue sarcoma lines recently established from fresh surgical biopsy specimens. These cell lines ranged from high susceptibility (939 melanoma) to strong resistance (A2058 melanoma and all three sarcomas) to tumour necrosis factor (TNF), an inducer of elevated intracellular Cer levels. However, all the cell lines demonstrated a dose-dependent susceptibility to C6-Cer with protracted cytotoxic kinetics, with the C8161 melanoma being the most sensitive and A2058 the least. Protein kinase C (PKC) antagonizes Cer-dependent apoptosis, and chelerythrine chloride, So and Sa, which inhibit PKC, caused extremely rapid cytotoxicity of melanoma cell lines, irrespective of their relative sensitivity to C6-Cer. So-mediated cytotoxicity was extensive even after only 90 min of treatment, within the time frame of limb perfusion. So and Sa only slightly potentiated the cytotoxic responses to TNF, C6-Cer or melphalan. Sphingolipid-driven intracellular pathways may offer opportunities for therapy of these tumours.
Department of Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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Auzenne
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Leroux
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Hu
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Pollock
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Feig
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Klostergaard
D000470:Alkaloids; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines; D002264:Carboxylic Acids / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D037341:Fumonisins; D018219:Histiocytoma, Benign Fibrous / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000473:pathology* / Q000503:physiopathology; D008558:Melphalan / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D012509:Sarcoma / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
D000470:Alkaloids; D053119:Benzophenanthridines; D002264:Carboxylic Acids; D002518:Ceramides; D037341:Fumonisins; D010617:Phenanthridines; D014409:Tumor Necrosis Factor-alpha; C101954:N-caproylsphingosine; C056933:fumonisin B1; C016299:chelerythrine; D011493:Protein Kinase C; D013110:Sphingosine; C005682:safingol; D008558:Melphalan