Skip to main content

Advertisement

SpringerLink
Log in

The antitrypanosomal drug melarsoprol competitively inhibits thiamin uptake in mouse neuroblastoma cells

  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

Melarsoprol is the main drug used for the treatment of late-stage sleeping sickness, although it causes severe side-effects such as encephalopathy and polyneuropathy leading to death in some patients. Recent data suggest that melarsoprol and its active metabolite melarsenoxide interfere with thiamin transport and metabolism in E. coli and yeast, but there are no data concerning their possible effects on thiamin metabolism in mammalian cells. We tested both drugs on thiamin transport in cultured mouse neuroblastoma cells using 14C-labeled thiamin. Melarsoprol, competitively inhibits high-affinity thiamin transport in mouse neuroblastoma cells with a Ki of 44 μmol/L. However, the active compound melarsenoxide has no inhibitory effect. This suggests that the side effects of melarsoprol treatment are unlikely to be due to inhibition of thiamin transport by melarsenoxide, its main metabolite in the brain.

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

Abbreviations

Mel B:

melarsoprol

Mel Ox:

melarsenoxide

References

  • Bettendorff L, Wins P. Mechanism of thiamin transport in neuroblastoma cells: Inhibition of a high affinity carrier by sodium channel activators and dependence of thiamine uptake on membrane potential and intracellular ATP. J Biol Chem. 1994;269:14379–85.

    CAS  PubMed  Google Scholar 

  • Blum J, Nkunku S, Burri C. Clinical description of encephalopathic syndromes and risk factors for their occurrence and outcome during melarsoprol treatment of human African trypanosomiasis. Trop Med Int Health. 2001;6:390–400.

    Article  CAS  PubMed  Google Scholar 

  • Carter NS, Fairlamb AH. Arsenical-resistant trypanosomes lack an unusual adenosine transporter. Nature 1993;361:173–6.

    Article  CAS  PubMed  Google Scholar 

  • Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD. Mutations in a new gene encoding a thiamine transporter cause thiamin-responsive megaloblastic anaemia syndrome. Nat Genet. 1999;22:309–12.

    Article  CAS  PubMed  Google Scholar 

  • Docampo R, Moreno SNJ. Current chemotherapy of human African trypanosomiasis. Parasitol Res. 2003;90:S10–3.

    PubMed  Google Scholar 

  • Dutta B, Huang W, Molero M, et al. Cloning of the human thiamin transporter, a member of the folate transporter family. J Biol Chem. 1999;45:31925–9.

    Article  Google Scholar 

  • Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH. Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Gen Metab. 2000;71:581–90.

    Article  CAS  Google Scholar 

  • Friedheim, EAH. Mel B in the treatment of human trypanosomiasis. Am J Trop Med. 1949;29:173–80.

    Google Scholar 

  • Hubert D, Barrett MP. Uptake and mode of action of drugs used against sleeping sickness. Biochem Parasitol. 2000;61:1–5.

    Google Scholar 

  • Keiser J, Ericsson O, Burri C. Investigations of the metabolites of the trypanocidal drug melarsoprol. Clin Pharmacol Ther. 2000;67:478–88.

    Article  CAS  PubMed  Google Scholar 

  • Klebe RJ Ruddle FH. Neuroblastoma: cell culture analysis of a differentiating stem cell system. J Cell Biol. 1969;43:69a.

    Google Scholar 

  • Mäser P, Sütterlin C, Kralli A, Kaminsky RA. A nucleoside transporter from Trypanosoma brucei involved in drug resistance. Science. 1999;285:242–44.

    Article  PubMed  Google Scholar 

  • Mäser P, Lüscher A, Kaminsky RA. Drug transport and drug resistance in African trypanosomes. Drug Resist Update. 2003;6:281–90.

    Article  Google Scholar 

  • Nok AJ. Arsenicals (melarsoprol), pentamidine and suramin in the treatment of human African trypanosomiasis. Parasitol Res. 2003;90:71–9.

    Article  PubMed  Google Scholar 

  • Peterson GL. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977;83:346–56.

    Article  CAS  PubMed  Google Scholar 

  • Rajgopal A, Edmondson A, Goldman D, Zhao R. SLC19A3 encodes a second thiamin transporter ThTr2. Biochim Biophys Acta. 2001;1537:175–8.

    CAS  PubMed  Google Scholar 

  • Said HM, Balamurugan K, Subramanian VS, Marchant JS. Expression and functional contribution of hTHTR-2 in thiamine absorption in human intestine. Am J Physiol Gastrointest Liver Physiol. 2004;286:G491–8.

    Article  CAS  PubMed  Google Scholar 

  • Schweingruber ME. The melaminophenyl arsenicals melarsoprol and melarsenoxide interfere with thiamin metabolism in the fission yeast Schizosaccharomyces pombe. Antimicrob Agents Chemother. 2004;48:3268–71.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Cellular and Molecular Neurobiology, University of Liège, Liège, Belgium

    P. Szyniarowski & L. Bettendorff

  2. Department of Analytical Biochemistry, Faculty of Biotechnology, Jagiellonian University, Cracow, Poland

    P. Szyniarowski

  3. Institute of Cell Biology, University of Bern, Bern, Switzerland

    M. E. Schweingruber

  4. Center for Cellular and Molecular Neurobiology, University of Liège, Bât. B36, Tour de Pathologie 2, étage +1, Avenue de l’Hôpital, 1, 4000, Liège 1 (Sart-Tilman), Belgium

    L. Bettendorff

Authors
  1. P. Szyniarowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Bettendorff
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. E. Schweingruber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Bettendorff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Szyniarowski, P., Bettendorff, L. & Schweingruber, M.E. The antitrypanosomal drug melarsoprol competitively inhibits thiamin uptake in mouse neuroblastoma cells. Cell Biol Toxicol 22, 183–187 (2006). https://doi.org/10.1007/s10565-006-0034-z

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-006-0034-z

Keywords

Search

Navigation