Trypanocidal activity of salinomycin is due to sodium influx followed by cell swelling

Particle and Fibre Toxicology

Darren W Sexton¹  Dietmar Steverding¹ 

[1] BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK

关键词: Drug screening;    Salinomycin;    Trypanosoma brucei;    African trypanosomiasis;   

Others  :  1228024
DOI  :  10.1186/1756-3305-6-78

 received in 2013-01-08, accepted in 2013-03-18,  发布年份 2013

【 摘 要 】

Background

The few currently available drugs for treatment of African trypanosomiasis are outdated and show problems with toxicity and resistance. Hence, there is an urgent need for the discovery and development of new anti-trypanosomal agents.

Findings

In this study, the ionophorous antibiotic salinomycin was investigated for its trypanocidal activity in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. The concentrations of salinomycin to reduce the growth rate by 50% and to kill the parasites were 0.31 μM and 1 μM, respectively. The trypanocidal action of the ionophore was shown to be the result of an influx of Na⁺ resulting in an increased intracellular Na⁺ concentration followed by cell swelling. This mode of action differs from the mechanism for the anti-cancer activity of salinomycin reported to be by induction of apoptosis.

Conclusion

Here we have shown that salinomycin is an effective agent against bloodstream forms of T. brucei and might be a potential candidate for treatment of African trypanosomiasis.

【 授权许可】

   
2013 Steverding and Sexton; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Molyneux DH, Pentreath V, Doua F: African trypanosomiasis in man. In Manson’s Tropical Diseases. 20th edition. Edited by Cook GC. London: W.B. Saunders; 1996:1171-1196.
• [2]World Health Organization: Trypanosomiasis, human African (sleeping sickness). World Health Org Fact Sheet 2012., 259http://www.who.int/mediacentre/factsheets/fs259/en/ webcite
• [3]Kristjanson PM, Swallow BM, Rowlands GJ, Kruska RL, de Leeuw PN: Measuring the costs of African animal trypanosomiasis, the potential benefits of control and returns to research. Agr Sys 1999, 59:79-98.
• [4]Delespaux V, de Koning HP: Drugs and drug resistance in African trypanosomiasis. Drug Resist Updat 2007, 10:30-50.
• [5]Caffrey CR, Steverding D: Recent initiatives and strategies to developing new drugs for tropical parasitic diseases. Expert Opin Drug Discov 2008, 3:173-186.
• [6]Miyazaki Y, Shibuya M, Sugawara H, Kawaguchi O, Hirose C, Nagatsu J, Esumi S: Salinomycin, a new polyether antibiotic. J Antibiot (Tokyo) 1974, 27:814-821.
• [7]Mitani M, Yamanishi T, Miyazaki Y: Salinomycin: a new monovalent cation ionophore. Biochem Biophys Res Commun 1975, 66:1231-1236.
• [8]Chapman HD: Use of anticoccidial drugs in broiler chickens in the USA: analysis for the years 1995 to 1999. Poult Sci 2001, 80:572-580.
• [9]Chapman HD, Johnson ZB: Use of antibiotics and roxarsone in broiler chickens in the USA: analysis for the years 1995 to 2000. Poult Sci 2002, 81:356-364.
• [10]Huczynski A: Salinomycin: a new cancer drug candidate. Chem Biol Drug Des 2012, 79:235-238.
• [11]Deterding A, Dungey FA, Thompson KA, Steverding D: Anti-trypanosomal activities of DNA topoisomerase inhibitors. Acta Trop 2005, 93:311-316.
• [12]Steverding D, Wang X: Trypanocidal activity of the proteasome inhibitor and anti-cancer drug Bortezomib. Parasit Vectors 2009, 2:29. BioMed Central Full Text
• [13]Steverding D, Wang X, Potts BC, Palladino MA: Trypanocidal activity of β-lactone-γ-lactam proteasome inhibitors. Planta Med 2012, 78:131-134.
• [14]Hirumi H, Hirumi K, Doyle JJ, Cross GAM: In vitro cloning of animal-infective bloodstream forms of Trypanosoma brucei. Parasitology 1980, 80:371-382.
• [15]Baltz T, Baltz D, Giroud C, Crockett J: Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense. EMBO J 1985, 4:1273-1277.
• [16]Moore GE, Gerner RE, Franklin HA: Culture of normal human leukocytes. J Am Med Assoc 1967, 199:519-524.
• [17]Finney DJ: Statistical method in biological assay. 3rd edition. London: Charles Griffin & Co; 1978.
• [18]Park JH, Schofield PJ, Edwards MR: Giardia intestinalis: volume recovery in response to cell swelling. Exp Parasitol 1997, 86:19-28.
• [19]Huczyński A, Janczak J, Antoszczak M, Wietrzyk J, Maj E, Brzezinski B: Antiproliferative activity of salinomycin and its derivatives. Bioorg Med Chem Lett 2012, 22:7146-7150.
• [20]Ketola K, Hilvo M, Hyötyläinen T, Vuoristo A, Ruskeepää AL, Orešič M, Kallioniemi O, Iljin K: Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br J Can 2012, 106:99-106.
• [21]Mosimann M, Goshima S, Wenzler T, Lüscher A, Uozumi N, Mäser P: A Trk/HKT-type K+ transporter from Trypanosoma brucei. Eukaryot Cell 2010, 9:539-546.
• [22]Nolan DP, Voorheis HP: Factors that determine the plasma-membrane potential in bloodstream forms of Trypanosoma brucei. Eur J Biochem 2000, 267:4615-4623.
• [23]Bassarak B, Uzcátegui NL, Schönfeld C, Duszenko M: Functional characterization of three aquaglyceroporins from Trypanosoma brucei in osmoregulation and glycerol transport. Cell Physiol Biochem 2011, 27:411-420.
• [24]Kim KY, Yu SN, Lee SY, Chun SS, Choi YL, Park YM, Song CS, Chatterjee B, Ahn SC: Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization. Biochem Biophys Res Commun 2011, 413:80-86.
• [25]Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA: Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci USA 2011, 108:13253-13257.
• [26]Nwaka S, Hudson A: Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov 2006, 5:941-955.
• [27]Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J: Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology 2012, 139:842-846.