Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

Blood Cells Mol Dis. 2015 Aug;55(2):119-26. doi: 10.1016/j.bcmd.2015.05.007. Epub 2015 May 27.

Abstract

Development of the antimalarial drug resistant strains has currently become a major public health challenge. There is an urgent need to develop new antimalarial drugs. Tyrosine kinase inhibitors (TKIs) are receiving increasing attention as anticancer therapy. It has revolutionarised the management of CML to say the least. TKIs are also increasingly being implicated in complicated but vital life cycle of malaria parasite. Hence we tested two commonly used but different classes of TKIs (imatinib and sorafenib) in-vitro for their antimalarial activity and possible synergistic activity with existing antimalarial drug. Antimalarial activity was tested with the help of modified WHO microtest technique in-vitro for five different Plasmodium falciparum laboratory strains (3D7, Dd2, 7G8, MRC2, PKL9). Imatinib and sorafenib showed a promising antimalarial activity with all the strains. These compounds caused dose dependent inhibition of parasite maturation. The isobologram analysis of the interactions of these TKIs with standard antimalarial drug, artesunate revealed distinct patterns of synergism, additivity and antagonism at different ratios. Imatinib showed worthwhile synergism with artesunate indicating imatinib and other tyrosine kinase inhibitors may have significant antimalarial activity and can be used in combination therapy.

Keywords: Artesunate; Combination therapy; Imatinib; Plasmodium falciparum; Tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / pharmacology*
  • Artemisinins / pharmacology
  • Artesunate
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Erythrocytes / parasitology
  • Humans
  • Imatinib Mesylate / pharmacology
  • Inhibitory Concentration 50
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / growth & development
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

  • Antimalarials
  • Artemisinins
  • Protein Kinase Inhibitors
  • Artesunate
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases