title: Targeting calcium homeostasis as the therapy of Chagas' disease and leishmaniasis - a review.
abstract: Ca(2+) has been largely recognized as an essential messenger in all eukaryotes, from   mammals to parasites. The disruption of Ca(2+) homeostasis in any cell usually drives to lethal   effects resulting in cell death by apoptosis or necrosis. This appears also to be the case in   human trypanosomatids, such as Trypanosoma cruzi, the causative agent of Chagas' disease,   Trypanosoma brucei, which produces "sleeping sickness" and Leishmania sp, responsible   for leishmaniasis. The aim of this review is to describe the intracellular Ca(2+) regulation and   the cytotoxic effect of new drugs regarding the disruption of Ca(2+) homeostasis in these   parasites. With regard to intracellular Ca(2+) regulation, all these trypanosomatids possess a   single mitochondrion that occupies 12% of the total volume of the parasite which is able to   accumulate large amounts of Ca(2+). The endoplasmic reticulum is also involved in Ca(2+) regulation.   These parasites also possess acidocalcisomes, an unusual organelle involved in the   bioenergetics of these cells in accumulating large amounts of polyphosphates together with   Ca(2+) ions. Trypanosomatids possess relatively large amounts of calmodulin. While this well   conserved protein is identical among all vertebrates, there is 89% amino acid sequence   identity between T. cruzi and vertebrate calmodulin. Recently, this protein has been cloned   and expressed from T. cruzi, allowing a further characterization corroborating significant   differences between calmodulin from T. cruzi and mammals. It has also been reported that a   commonly used antiarrhytmic, amiodarone, which is used in chronic Chagas' patients with   heart problems, is able to produce a large trypanocidal effect. The intracellular compartments   responsible for the increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) upon the addition   of amiodarone are the single large mitochondrion and the acidocalcisomes. Amiodarone is   also capable to inhibit the oxidosqualene cyclase, a key enzyme in the synthesis of ergosterol.   The effect of amiodarone was highly synergistic with posaconazole, a known potent inhibitor   of the synthesis of ergosterol. Interestingly, posaconazole by itself is able to produce an   increase in the [Ca(2+)](i). Concerning putative treatments in humans, amiodarone was reported   to induce the cure of a patient with Chagas' disease, when used in combination with   itraconazole. Seemingly, a recent case indicated the cure of a patient with Chagas' disease by   the administration of posaconazole. Miltefosine, an orally active alkyl-lysophospholipid with   potent anti-Leishmania activity, represents a major advance in the treatment of leishmaniasis.   Recently it was reported that miltefosine also disrupts the parasite's intracellular Ca(2+)   homeostasis, by inducing a large increase in [Ca(2+)](i), through the activation of a plasma   membrane Ca(2+) channel. It has been found that the combination of miltefosine and amiodarone   have synergistic effects on the proliferation of amastigotes growing inside macrophages and   this led to 90% of parasitological cure in a murine model of leishmaniasis, as revealed by a   PCR assay. More recently, posaconazole has been used successfully in a case of a human Old   World cutaneous leishmaniasis. All these findings strongly suggest that the alteration of the   intracellular Ca(2+) homeostasis of these parasites is a promising strategy as a target of new as   well as repurposed old-known drugs.
authors.affiliation: Instituto de Estudios Avanzados (IDEA), Carretera Nacional Hoyo de la Puerta, Baruta, Caracas, Venezuela. gbenaim@idea.gob.ve
authors.forename: B  Gustavo
authors.initials: B
authors.lastname: Benaim
authors.forename: Célia R S
authors.initials: CR
authors.lastname: Garcia
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D014355:Chagas Disease / Q000188:drug therapy; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007891:Leishmania / Q000187:drug effects / Q000378:metabolism*; D007896:Leishmaniasis / Q000188:drug therapy; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000981:Antiprotozoal Agents; D014230:Triazoles; D010767:Phosphorylcholine; C039128:miltefosine; C101425:posaconazole; D000638:Amiodarone; D002118:Calcium