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

AbstractOBJECTIVES:
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.
AuthorsLisa Sanderson, Vanessa Yardley, Simon L Croft
JournalThe Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 69 Issue 7 Pg. 1888-91 (Jul 2014) ISSN: 1460-2091 [Electronic] England
PMID24668412 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected].
Chemical References
  • Antineoplastic Agents
  • Antiprotozoal Agents
  • Indoles
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyrroles
  • Quinazolines
  • Lapatinib
  • Niacinamide
  • Sorafenib
  • Sunitinib
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Antiprotozoal Agents (pharmacology, therapeutic use)
  • Disease Models, Animal
  • Drug Repositioning
  • Indoles (pharmacology, therapeutic use)
  • Inhibitory Concentration 50
  • Lapatinib
  • Leishmania (drug effects)
  • Leishmaniasis (drug therapy)
  • Mice, Inbred BALB C
  • Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
  • Phenylurea Compounds (pharmacology, therapeutic use)
  • Protein Kinase Inhibitors (pharmacology, therapeutic use)
  • Pyrroles (pharmacology, therapeutic use)
  • Quinazolines (pharmacology, therapeutic use)
  • Sorafenib
  • Sunitinib
  • Treatment Outcome

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