New Approaches for the Identification of Drug Targets in Protozoan Parasites - International Review of Cell and Molecular Biology - page 385

Concerning apicomplexan parasites, several studies have shown that not
only nitazoxanide but also some of its derivatives lacking the nitro group
exhibit in vitro activity against the intracellular apicomplexan parasites N.
caninum ( Esposito et al., 2007 ), C. parvum ( Gargala et al., 2010 ), Besnoitia
besnoiti ( Cortes et al., 2007 ), Leishmania ( Zhang et al., 2010 ), Plasmodium
sp. and Trypanosoma sp. ( Navarrete-Vazquez et al., 2011 ). The same affinity
chromatography approach as with G. lamblia has been performed with N.
caninum , and a protein disulfide isomerase, a protein with affinities to a vari-
ety of hydrophobic compounds including hormones ( Primm and Gilbert,
2001 ), has been identified as nitazoxanide-binding protein ( Müller et al.,
2008b ). Thus, a clear target for thiazolides in apicomplexan is still unknown.
Nitazoxanide and some non-nitro-derivatives are, however, toxic to pro-
liferating host cells. By affinity chromatography, glutathione-S-transferase
P1 (GSTP) has been identified as a thiazolide-binding protein in Caco2
cells, and inhibition of GSTP activity by nitazoxanide and some non-nitro-
thiazolides is well correlated with the efficacy of these drugs to induce apop-
tosis. Overexpression and downregulation of GSTP is correlated with an
increase or decrease of sensitivity, respectively ( Müller et al., 2008c ). GSTP
regulates cellular stress responses and apoptosis by sequestering and inacti-
vating c-Jun N-terminal kinase (JNK). Thiazolides induce expression and
activation of a critical downstream target of JNK, Bim, in a JNK-dependent
manner. If Bim is downregulated, thiazolide-induced apoptosis is blocked
( Sidler et al., 2012 ). Sublethal concentrations of thiazolides enhance the
proapoptotic effect of tumor necrosis factor.
Moreover, in human foreskin fibroblasts, quinone reductase 1 has been
identified as a thiazolide-binding protein ( Müller and Hemphill, 2011b ).
These findings suggest that NTZ and related thiazolides exert their effects
against intracellular protozoa indirectly by activating innate immune
responses in the host cells rather than directly by affecting the pathogen
itself.
4.2. Mefloquine, Another Compound with Different Targets
The quinolines mefloquine, chloroquine and related compounds are well-
established antimalarials ( Brocks and Mehvar, 2003 ; Milner et al., 2010 ).
Their mode of action is reported to rely on the interference with hemoglo-
bin digestion by the parasite ( Foley and Tilley, 1998 ). Mefloquine is effective
not only against Plasmodium sp . but also against Schistosoma mansoni adult
worms, where it inhibits the formation of hemozoin, a heme detoxifica-
tion aggregate ( Oliveira et al., 2004 ), and against juvenile stages ( Keiser