Safingol (L-threo-dihydrosphingosine), a saturated optical isomer of naturally occurring sphingosine, is an inhibitor of protein kinase C (PKC) that competitively interacts at the regulatory phorbol binding domain of PKC.^1,2 Recently, safingol has been demonstrated to act synergistically with fenretinide (4-HPR), a drug which induces large amounts of the pro-death lipid, ceramide.³ It is thought that safingol's inhibition of PKC-z may disrupt pro-life feedback loops allowing manipulation of intracellular ceramide levels and thus increasing the cytotoxic effect of 4-HPR. Increased cytotoxicity has been observed in numerous cell lines, including p53 non-functional, chemotherapy-resistant lines, at drug levels minimally toxic to normal fibroblasts and bone marrow. It has also been reported that enhanced drug accumulation and sensitivity in MCF-7 DOXR cells treated with safingol correlates with inhibition of PKC rather than competitive interference with P-gp drug binding through direct interaction with P-glycoprotein.² In an earlier pilot clinical study, it was found that safingol could be given safely with doxorubicin, and the effects of doxorubicin were potentiated by coadministration of safingol.⁴ In a separate study, safingol not only potentiated the toxicity of doxorubicin, but the toxic effect was noted for cisplatin against tumor cells in vitro and in vivo.⁵ In gastric cancer cells, safingol enhanced the cytotoxic effect of the chemotherapeutic agent mitomycin C by promoting drug-induced apoptosis, regardless of the drug resistance status of the cells.⁶

References:

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2. Sachs, C.W., A.R. Safa, S.D. Harrison, and R.L. Fine. (1995). Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C. J Biol Chem 270:26639-48.
   
3. Maurer, B.J., M.C. Cabot, C. P. Reynolds (2000). Modulators of Ceramide Metabolism Synergize Fen- retinide Cytotoxicity in Multiple Tumor Cell Types. AACR Annual Meeting Abstracts 1520.
   
4. Schwartz, G.K., D. Ward, L. Saltz, E.S. Casper, T. Spiess, E. Mullen, J. Woodworth, R. Venuti, P. Zervos, A.M. Storniolo, and D.P. Kelsen. (1997). A pilot clinical/pharmacological study of the protein kinase C- specific inhibitor safingol alone and in combination with doxorubicin. Clin Cancer Res 3:537-43.
   
5. Kedderis, L.B., H.P. Bozigian, J.M. Kleeman, R.L. Hall, T.E. Palmer, S.D. Harrison Jr, and R.L. Susick Jr. (1995). Toxicity of the protein kinase C inhibitor safingol administered alone and in combination with chemotherapeutic agents. Fundam Appl Toxicol 25:201-17.
   
6. Schwartz, G.K., A. Haimovitz-Friedman, S.K. Dhupar, D. Ehleiter, P. Maslak, L. Lai, F. Loganzo Jr, D.P. Kelsen, Z. Fuks, and A.P. Albino. (1995). Potentiation of apoptosis by treatment with the protein kinase C-specific inhibitor safingol in mitomycin C-treated gastric cancer cells. J Natl Cancer Inst 87:1394-9.