Glucosylceramides

The glycosphingolipids (GSLs) are sugar-containing lipids built on a backbone of ceramide they include galactosyl- and glucosylceramide (cerebrosides) and the gangliosides. Their structures are described in Chapter 14. They are mainly located in the plasma membranes of cells. 

In MDR cells, a significant fraction of P-gp is found associated with caveolin-rich membranes, and there is a substantial increase in the number of caveolae and caveolin-1 protein level. For example, both multidrug resistant human colon adenocarcinoma HT-29 cells and adriamycin-resistant breast adenocarcinoma MCF-7 cells display about a 12-fold increase in caveolin expression, which correlates with an approximate fivefold increase in morphologically identifiable caveolae [55], In addition, these cells exhibit increased amounts of phospholipase D and lipids such as cholesterol, glucosylceramide, and sphingomyelin [56, 57], Similarly, taxol-resistant A549 cells display both increased caveolin expression and caveolae numbers [58], While these correlations track with MDR, they do not suggest a simple mechanism for the role of... 

Liu, Y.Y., Han, T.Y., Giuhano, A.E. and Cabot, M.C., 1999, Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J. Biol. Chem. 274 1140-1146. 

The intracellular CER concentration results from the equilibrium between CER production and CER metabohsm It now appears that CER metabolism plays a critical role in regulating intracellular CER concenttation and therefore effector-induced cytotoxicity. The four major CER metabolic pathways include its reconversion into SM, its catabohsm to sphingosine (followed by sphingosine 1-phosphate) and its metabolism to glucosylceramide or galactosylceramide. All of which may conttibute to limiting stress-induced CER elevation, except for the galactosylceramide pathway which has of yet not been described. 

Rani, C. S., Abe, A., Chang, Y., Rosenzweig, N., Saltiel, A. R., Radin, N. S., and Shayman, J. A., 1995, Cell cycle arrest induced by an inhibitor of glucosylceramide synthase. Correlation with cyclin-dependent kinases. J. Biol. Chem. 270 2859-2867. 

Miglustat (60 Zavesca ) 1 -Deoxynoj irimycin (DNJ) Iminosugar Semi-synthetic NP Microbial Type 1 Gaucher disease (GDI) Inhibits glucosylceramide synthase activity 215-217, 525-531... 

GALACTOSIDE FUCOSYLTRANSFERASES GALACTOSIDE SIALYLTRANSFERASES /3-D-Galactosyl-1,4-y3-D-glucosylceramide, SIALYLTRANSFERASE "GAMESS,"... 

GLUCOSE TRACER KINETICS Glucosylceramide j8-D-glucosidase, GLUCOCEREBROSIDASE GLUCURONATE-1-PHOSPHATE URIDYLYL-TRANSFERASE... 

Fig. 2. Mechanisms causing resistance to antitumor treatment. ATM. ataxia telangiectasia gene, (Westphal et al., 1998 Xu and Baltimore, 1996), bcl-2/bax (Farrow and Brown, 1996, Zunino et al., 1997 Haq and Zanke, 1998), bcr/abl (McGahon et al., 1994), BCRP, breast cancer resistance protein (Doyle et d., 1998 Ross et al, 1999) bleomycin hydrolase (El-Deiry, 1997), BRCAl (Husain et al., 1998 Chen et al., 1998), BRCA2 (Chen et al., 1998 Chen et 1999), c-abl (White and Prives, 1999), c-jun (Sanchez-Perez and Perona, 1999), cytidine deaminase (El-Deiry, 1997), DNA poip, DNA polymerase p (Ochs et al., 1999), dihydrofolate reductase (Schimke, 1986), DT-diaphorase (Riley and Workman, 1992 Fitzsimmons et al., 1996 El-Deiry, 1997), EGR-1 (Ahmed et al., 1996), fos (Niimi et al., 1991), glucosylceramide synthase...

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