Sphingolipids

Details Sphingolipids Sphingolipids

2002-10-17

2004-06-29

Carr, Deborah D. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S055000, C558S166000, C564S305000, C564S188000, C568S939000, C514S623000, C514S642000, C514S645000, C514S660000, C514S661000

Reexamination Certificate

active

06756504

ABSTRACT:

BACKGROUND OF THE INVENTION
Sphingolipids (SL) comprise a group of lipids having ceramide, i.e., N-acylsphingosine as the basic group. There are two main types of SL, phosphoSL and glycoSL. While the former have one main component, i.e., sphingomyelin (ceramide-phosphorylcholine), the glycosphingolipids comprise a wide group. They range from monohexosylceramides (ceramide &bgr;-glucose and ceramide &bgr;-galactose), through oligohexosyl ceramide (e.g., di- and trihexosyl ceramides) to a large number of gangliosides composed of oligohexosyl ceramides to which sialic acid is also linked. SLs are present in practically every cell type and tissue and particularly abound in the nervous system. The relative composition of the SL may change with age; thus, it has been shown that the ratio of sphingomyelin to lecithin increases with age.
Glycosphingolipids have a high binding potential and act as specific receptors for a number of external agents, e.g., lectins, toxins, hormones and viruses. To exemplify: vibrio cholerae toxin links to GMI-ganglioside and Shigella dysenteriae verotoxins to globotriaosyl ceramide.
During the past decade there has been an enormous increase in research on sphingolipids due to discoveries that implicated members of this group in signal transduction processes [recently reviewed in Levade et al.,
Biochim. Biophys. Acta
1438, 1-17 (1999); Mathias et al.,
Biochem. J.
335, 465-480 (1998); Perry et al.,
Biochim. Biophys. Acta
1436, 233-243 (1998); Riboni et al.,
Prog. Lipid Res.
36, 153-195 (1997)]. The most studied compound was ceramide which was shown to play a role in the regulation of key processes such as growth inhibition, differentiation and apoptosis [Hannun et al.,
Biochim. Biophys. Acta
1154, 223-236; Hannun et al.,
Trends Cell Biol.
10, 73-80 (2001); Higgins et al.,
Trends Biochem. Sci.
17, 18-21 (1992)]. SPM is generally considered as the primary metabolic source of ceramide whose generation in a particular location in the cell, (e.g., the membrane) makes it suitable for mediating cellular signaling processes. An increased de novo synthesis of ceramide has also been described as a potential source for signaling [Bose et al.,
Cell
82, 405-414, (1995)]. Therefore, a major effort has been directed to modulate the generation of intracellular ceramide by sphingomyelinases, mostly the neutral, membrane-bound enzyme, although the acidic enzyme has also been implicated. Nevertheless, it should be emphasized that modification of the biosynthetic mechanisms such as reduction of the conversion of ceramide to SPM or glycolipids and, in parallel, its hydrolysis by ceramidases would also increase its concentration in the cell.
The role of sphingolipids in signal transduction [reviewed in L. Riboni et al.,
Prog. Lipid Res.
36, 153-195 (1997) and A. Gomez-Munoz,
Biochim. Biophys. Acta
1391, 32-109 (1998)] have been extensively studied, and was proposed to operate through the “sphingomyelin cycle”. According to this hypothesis, binding a particular extracellular ligand to its receptor activates a plasma membrane-bound sphingomyelinase, giving rise to ceramide, which acts as a mediator of the intracellular effects of the ligand. Numerous publications describe and emphasize the role of ceramide in cell killing by apoptosis as well as its effect on important cellular events such as proliferation, differentiation and reaction to stress conditions. Of particular interest are also reports that short chain, cell-permeable (e.g., C
2
or C
6
) ceramides evoke biological responses that lead to cell killing. Other studies, using the precursor of ceramide, i.e., sphingosine have shown its effects on cell growth and viability. Furthermore, sphingosine was shown to inhibit protein kinase C and increase the intracellular concentration of calcium ions. The phosphorylated form of sphingosine, i.e., sphingosine-1-phosphate has been shown to be a potent activator of phospholipase D. And di- or tri-methylated sphingosine was shown to inhibit growth of cancer cells [Endo et al.,
Cancer Research
51, 1613-1618, (1981)].
The involvement of ceramide and sphingolipid metabolism in cancer has been studied. It have been demonstrated that apoptosis induced by administration of a variety of chemotherapeutic agents is mediated by ceramide [Strum et al.,
J. Biol. Chem.
269, 15493-15497 (1994); Maurer et al.,
J. Natl. Cancer Inst.
91, 1138-1146 (1999); Suzuki et al.,
Exp. Cell Res.
233, 41-47 (1997)]. Anthracyclins (e.g., daunorubicin) have been shown to induce ceramide accumulation which subsequently led to death of cancer cells [Bose et al.,
Cell
82, 405-414 (1995)]. The second line of study showed that drug-resistant cancer cells differ in their sphingolipid metabolism from drug-sensitive ones. Of special interest in this respect are studies of Cabot et al. [Lavie et al.,
J. Biol. Chem.
271, 19530-19536 (1996)], who have demonstrated that glucosylceramide, a direct metabolic product of ceramide, was elevated in several drug-resistant cells overexpressing the P-glycoprotein pump (Pgp). Overexpression of the enzyme that synthesizes this glycolipid, i.e., glucosylceramide synthetase (GCS), by a retroviral expression system resulted in conversion of doxorubicin-sensitive cells into resistant ones [Liu et al.,
J. Biol. Chem.
274, 1140-1146 (1999)]. Conversely, inhibition of GCS expression, by antisense technology, resulted in increased sensitivity to doxorubicin. Cabot et al. have also proposed that drug-resistance modulators such as tamoxifen, verapamil and the cyclosporine analog, PSC 833, exert their effect by inhibition of GCS [Cabot et al.,
FEBS Letters
394, 129-131 (1996),
FEBS Letters
431, 185-199 (1998); Lavie et al.,
J. Biol. Chem.
272, 1682-1687 (1999); Lucci et al.,
Cancer
86, 300-311 (1999)], resulting in an increase of cellular ceramide. Nicholson et al. (
British J. Cancer
81, 423-430 (1989)] have shown that an inhibitor of GCS, 1-phenyl-2-decanoyl-amino-3-morpholino-1-propanol, killed preferentially multidrug-resistant cells, compared to their drug-sensitive counterparts. Taken together, the above studies suggest a metabolic mechanism which in MDR-cells decrease their ceramide content by converting it to glucosylceramide, making them resistant to a series of chemotherapeutic drugs.
Of special interest is the mechanism proposed for the anticancer drug hexadecylphosphocholine [HePC, Wieder et al.,
J. Biol. Chem.
273, 11025-11031, (1998)]. This is an antiproliferative drug, which is currently used for the treatment of extraneous metastases of mammary carcinoma and has been shown to induce apoptosis at a concentration of 25 &mgr;M. The above publication provides support that HePC, which inhibits the biosynthesis of phosphatidylcholine exerts a secondary effect by decreasing the biosynthesis of sphingomyelin and consequently increasing the levels of ceramide and it is probably the latter that is responsible for the proapoptotic properties of HePC. And, indeed the authors showed that the PC-induced apoptosis was blocked by Fumonisin B1, an inhibitor of ceramide synthesis. And, short-chain, membrane-permeable ceramides additively increased the apoptotic effect of HePC.
Another major aspect of the metabolism of the sphingolipids is their accumulation in organs of patients afflicted with the genetic lipid storage diseases, such as Gaucher disease (&bgr;-glucosidase), Tay-Sachs disease (&bgr;-N-acetyl hexosaminidase); Niemann-Pick disease (acid sphingomyelinase), Krabbe disease (&bgr;-galactosidase), Metachromatic leukodystrophy (arylsulfatase A), Fabry disease (ceramidase) and Farber disease (&agr;-galactosidase). Each of these diseases is due to a mutation in a gene encoding a lysosomal sphingolipid hydrolase (shown in brackets). Consequently, the activity of the respective hydrolase is considerably reduced resulting in accumulation of the respective sphingolipid in the patients' organs.
Being a metabolic disorder, the metabolic

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