Skip to main content
SpringerLink
Log in

Treating glucosphingolipid disorders by chemotherapy: Use of approved drugs and over-the-counter remedies

  • Published:
Journal of Inherited Metabolic Disease

Abstract

The accumulation of a glucosphingolipid (GSL) in individuals lacking an adequate level of hydrolase activity could be minimized by chemotherapeutic measures that slow the formation of the GSL and stimulate the defective hydrolase. By achieving a balance in the rates of formation and breakdown, one should be able to alleviate the symptoms of excess storage and achieve a satisfactory accommodation. While several drugs seem to be specifically suitable for this purpose, only one of these has been approved for human use. However, less effective drugs and over-the-counter substances are available for human use and may prove satisfactory for a few years until better ones are made available. The proposed materials and the evidence behind the recommendations are presented in this paper.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Abe A, Arend LJ, Lee L, Lingwood C, Brady RO, Shayman JA (2000a) Glycosphingolipid depletion in Fabry disease lymphoblasts with potent inhibitors of glucosylceramide synthase. Kidney Int 57: 446–454.

    Google Scholar 

  • Abe A, Gregory S, Lee L, et al (2000b) Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest 105: 1563–1571.

    Google Scholar 

  • Andersson U, Butters TD, Dwek RA, Platt FM (2000) N-Butyldeoxygalactonojirimycin: a more selective inhibitor of GSL biosynthesis than N-butyldeoxynojirimycinin vitro and in vitro. Biochem Pharmacol 59: 821–829.

    Google Scholar 

  • Andrieu-Abadie N, Jaffreézou JP, Hatem S, Laurent G, Levade T, Mercadier JJ (1999) L-Carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: role of inhibition of ceramide generation. FASEB J 13: 1501–1510.

    Google Scholar 

  • Cabot MC, Giuliano AE, Volner A, Han TY (1996) Tamoxifen retards glycosphingolipid metabolism in human cancer cells. FEBS Lett 394: 129–131.

    Google Scholar 

  • Chatterjee S, Cleveland T, Shi WY, Inokuchi J, Radin NS (1996) Studies of the action of ceramide-like substances (D- and L- threo-PDMP) on sphingolipid glycosyltransferases and purified lactosylceramide synthase. Glycoconjugate J 13: 481–486.

    Google Scholar 

  • Cifone MG, Migliorati G, Parroni R, et al (1999) Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C acidic sphingomyelinase and caspases. Blood 93: 2282–2296.

    Google Scholar 

  • Cox T, Lachmann R, Hollak C, et al (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 353: 1481–1485.

    Google Scholar 

  • Datta SC, Radin NS (1988) Normalization of liver glucosylceramide levels in the "Gaucher" mouse by phosphatidylserine injection. Biochem Biophys Res Commun 152: 155–160.

    Google Scholar 

  • El Bawab S, Bielawska A, Hannun YA (1999) Purification and characterization of a membrane-bound nonlysosomal ceramidase from rat brain. J Biol Chem 274: 27948–27955.

    Google Scholar 

  • El Etreby MF, Liang Y (1998) Effect of antiprogestins and tamoxifen on growth inhibition of MCF-7 human breast cancer cells in nude mice. Breast Cancer Res Treat 49: 109–117.

    Google Scholar 

  • El-Khatib M, Radin NS, Shayman JA (1996) Glycosphingolipid synthesis and proliferation in a renal cell line grown in high glucose. Am J Physiol 270 (Renal Fluid Electrolyte Physiol 39): F476-F484.

    Google Scholar 

  • Fenderson BA, Ostrander GK, Hausken Z, Radin NS, Hakomori S (1992) A ceramide analog (PDMP) inhibits glycolipid synthesis in fish embryos. Exp Cell Res 198: 362–366.

    Google Scholar 

  • Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Medicine 6: 313–319.

    Google Scholar 

  • Gonzalez F, Amos H (1977) Effects of naturally occurring sugars on Ehrlich ascites tumor growth in mice. J Natl Cancer Inst 58: 1519–1522.

    Google Scholar 

  • Hickson-Bick DLM, Buja LM, McMillin JB (2000) Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. J Mol Cell Cardiol 32: 511–519.

    Google Scholar 

  • Hospattankar AV, Vunnam RR, Radin NS (1982) Changes in liver lipids after administration of 2-decanoylamino-3-morpholinopropiophenone and chlorpromazine. Lipids 17: 538–543.

    Google Scholar 

  • Inokuchi J, Mason I, Radin NS (1987) Antitumor activity in mice of an inhibitor of glycosphingolipid biosynthesis. Cancer Lett 38: 23–30.

    Google Scholar 

  • Jeyakumar M, Butters TD, Cortina-Borja M, et al (1999) Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc Natl Acad Sci USA 96: 6388–6393.

    Google Scholar 

  • Kobayashi T, Shinnoh N, Goto I, et al (1985) Galactosylceramide-and lactosylceramide-loading studies in cultured fibroblasts from normal individuals and patients with globoid cell leukodystrophy (Krabbe's disease) and GM1-gangliosidosis. Biochim Biophys Acta 835: 456–464.

    Google Scholar 

  • Koide SS (1998) Mifepristone—auxiliary therapeutic use in cancer and related disorders. J Reprod Med 43: 551–560.

    Google Scholar 

  • Lavie Y, Cao H, Volner A, et al (1977) Agents that reverse multidrug resistance, tamoxifen, verapamil, and cyclosporin A, block glycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells. J Biol Chem 272: 1682–1687.

    Google Scholar 

  • Lee L, Abe A, Shayman JS (1999) Improved inhibitors of glucosylceramide synthase. J Biol Chem 274: 14662–14669.

    Google Scholar 

  • Levi M, Shayman JA, Abe A, et al (1995) Dexamethasone modulates rat renal brush border membrane phosphate transporter mRNA and protein abundance and GSL composition. J Clin Invest 96: 207–216.

    Google Scholar 

  • LeVine SM, Pedchenko TV, Bronshteyn IG, Pinson DM (2000) L-Cycloserine slows the clini-cal and pathological course in mice with globoid cell leukodystrophy (twitcher mice). J Neurosci Res 60: 231–236.

    Google Scholar 

  • Liu B, Hannun YA (1997) Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 272: 16281–16287.

    Google Scholar 

  • Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA (1988) Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem 273: 11313–11320.

    Google Scholar 

  • Lucci A, Han TY, Liu YY, Giuliano AE, Cabot MC (1999) Modification of ceramide metab-olism increases cancer cell sensitivity to cytotoxics. Int J Oncol 15: 541–546.

    Google Scholar 

  • Ma Q, Williamson KE, O'Rourke D, Rowlands BJ (1999) The effects of L-arginine on crypt cell hyperproliferation in colorectal cancer. J Surg Res 81: 181–188.

    Google Scholar 

  • Madison KC, Sando GN, Howard EJ, et al (1998) Lamellar granule biogenesis: a role for ceramide glucosyltransferase, lysosomal enzyme transport, and the Golgi. J InvestDermatol Symp Proc 3: 80–86.

    Google Scholar 

  • Maurer BJ, Metelitsa LS, Seeger RC, Cabot MC, Reynolds CP (1999) Increase of ceramide and induction of mixed apoptosis necrosis by N-(4-hydroxyphenyl)-retinamide in neuroblastoma cell lines. J Natl Cancer Inst 91: 1138–1146.

    Google Scholar 

  • Platt FM, Butters TD (1998) New therapeutic prospects for the glycosphingolipid lysosomal storage diseases. Biochem Pharmacol 56: 421–430.

    Google Scholar 

  • Platt FM, Neises GR, Reinkensmeier G, et al (1997) Prevention of lysosomal storage in Tay Sachs mice treated with N-butyldeoxynojirimycin. Science 276: 428–431.

    Google Scholar 

  • Radin NS (1996) Treatment of Gaucher's disease with an enzyme inhibitor. Glycoconjugate J 13: 153–157.

    Google Scholar 

  • Radin NS (1999) Chemotherapy by slowing glucosphingolipid synthesis. Biochem Pharmacol 57: 589–595.

    Google Scholar 

  • Shukla A, Shukla GS, Radin NS (1992) Control of kidney size by sex hormones; possible involvement of glucosylceramide. Am J Physiol 262: F24-F29.

    Google Scholar 

  • Shukla G, Shukla A, Inokuchi J, Radin NS (1991) Rapid kidney changes resulting from glycosphingolipid depletion by treatment with a glucosyltransferase inhibitor. Biochim Biophys Acta 1083: 101–108.

    Google Scholar 

  • Sonntag WE, Lynch CD, Cefalu WT, et al (1999) Pleiotropic effects of growth hormone and insulin-like growth factor IGF-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol A Biol Sci Med Sci 54: B521-B538.

    Google Scholar 

  • Surette ME, Fonteh AN, Bernatchez C, Chilton FH (1999) Perturbations in the control of cellular arachidonic acid levels block cell growth and induce apoptosis in HL-60 cells. Carcinogenesis 20: 757–763.

    Google Scholar 

  • Zador IZ, Deshmukh GD, Kunkel R, Johnson K, Radin NS, Shayman JA (1993) A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus. J Clin Invest 91: 797–803.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Mental Health Research Institute, The University of Michigan, Ann Arbor, Michigan, USA

    N. S. Radin

Authors
  1. N. S. Radin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radin, N.S. Treating glucosphingolipid disorders by chemotherapy: Use of approved drugs and over-the-counter remedies. J Inherit Metab Dis 23, 767–777 (2000). https://doi.org/10.1023/A:1026796200760

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026796200760

Keywords

Search

Navigation