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J Antimicrob Chemother. 2014 Jul;69(7):1888-91. doi: 10.1093/jac/dku069. Epub 2014 Mar 25.

Activity of anti-cancer protein kinase inhibitors against Leishmania spp.

Author information

1
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
2
Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK vanessa.yardley@lshtm.ac.uk.

Abstract

OBJECTIVES:

There is an urgent need to develop new and effective treatments for poverty-related neglected diseases. In light of the time required to bring a new drug to market and the cost involved (10-15 years, >1 billion US$), one approach to identifying new treatments for diseases like leishmaniasis is to evaluate drugs that are already registered for the treatment of other diseases. This paper describes the anti-leishmanial activities of 10 FDA-approved protein kinase inhibitors already available for the treatment of human cancers.

METHODS:

In vitro and in vivo models of Leishmania infection were used to evaluate the potency of selected protein kinase inhibitors.

RESULTS:

Sunitinib, sorafenib and lapatinib were identified as active against Leishmania donovani amastigotes in cultured murine macrophages with IC(50) values of 1.1, 3.7 and 2.5 μM, respectively, a level of potency similar to that of miltefosine (IC(50) = 1.0 μM), and were not toxic to mammalian cells. In addition, some of the protein kinase inhibitors were active against L. donovani in the BALB/c mouse model of infection; dosing on days 7-11 with a 50 mg/kg oral dose of sunitinib, lapatinib or sorafenib reduced liver amastigote burdens by 41%, 36% and 30%, respectively, compared with untreated control mice. Although less efficacious, sorafenib was also active in vitro against intracellular amastigotes of the cutaneous disease-causing species Leishmania amazonensis, Leishmania major and Leishmania mexicana.

CONCLUSIONS:

This study demonstrates in vivo anti-leishmanial activity of clinically used protein kinase inhibitors and provides further evidence of the potential of drug repurposing.

KEYWORDS:

PP2; drug repurposing; lapatinib; sorafenib; sunitinib

PMID:
24668412
DOI:
10.1093/jac/dku069
[Indexed for MEDLINE]

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