Application Notes:
N-Hexanoyl-NBD-L-threodihydrosphingosine
is a
synthetic dihydroceramide
analog containing the 7-(4-
nitrobenzo-2-oxa-1,3-diazole)
(NBD) fluorescent group. NBD
has been shown to have only a
small influence on lipid
adsorption into cells and cellular
membranes in many
applications. This fluorescent analog of L-threo-dihydroceramide is comparable to C6:0-L-threo-dihydroceramide in some
biological functions. Safingol is a fully saturated, non-natural analog of sphingosine that has anticancer properties and is
being investigated for its potential as an antitumor therapy. It has been shown to inhibit both protein kinase C (PKC) and
sphingosine kinase. Safingol competitively interacts at the regulatory phorbol-binding domain of PKC, a kinase involved in
tumorigenesis. Safingol has been shown to potentiate the effect of doxorubicin (DOX) in tumor-bearing animals.1 It has
been reported that safingol is able to increase the activity of DOX and other chemotherapeutic agents, including mitomycin
C, by generating the pro-apoptotic second messenger ceramide, even in tumor cell lines that were resistant to chemotherapy
due to mutations.2 However, a study has recently claimed that safingol induces cell death of an exclusively autophagic
character and lacking any of the hallmarks of apoptosis.3 Safingol inhibited the reactive oxygen intermediates (ROI) released
from isolated neutrophils and phorbol ester-induced edema and neutrophil influx. Safingol also demonstrates antiinflammatory
activity. Safingol, like the natural D-erythro-sphinganine, is used as a biosynthetic precursor for all complex
sphingolipids althogh the metabolism of the natural and the non-natural compounds are different.4
References:
1. Darges, et al. “Inhibition of leukotriene B4 (LTB4) in human neutrophils by L-threo-dihydrosphingosine” Adv. Exp. Med. Biol, Vol. 400A pp. 387-392,
1997
2. G. Schwartz, et al. “A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin”
Clin. Cancer Res, Vol. 3 pp. 537-543, 1997
3. J. Coward et al. “Safingol (L-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway”
Autophagy Vol. 5(2) pp.184-193, 2009
4. M. Dragusin et al. “Metabolism of the unnatural anticancer lipid safingol,L-threo-dihydrosphingosine, in cultured cells” Vol. 44 pp. 1772, 2003