Identification of a sphingosine-sensitive Ca2+ channel in the plasma membrane of Leishmania mexicana

Benaím, Gustavo; García-Marchán, Yael; Reyes, Claudia; Uzcanga, Graciela L.; Figarella, Katherine

doi:10.1016/j.bbrc.2012.12.033

Cited by 25 publications

(41 citation statements)

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“…It has been proposed that disruption of parasite intracellular Ca 2ϩ homeostasis is the target of action of several drugs, including miltefosine and amiodarone (7). Thus, miltefosine opens a Ca 2ϩ channel in the plasma membrane of these parasites (6), probably related to the recently described sphingosine-induced L-type voltage-dependent Ca 2ϩ channel in L. mexicana (8), causing a large increase in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) of the parasites, while amiodarone also increases the [Ca 2ϩ ] i in L. mexicana promastigotes, by collapsing the mitochondrial electrochemical potential and alkalinizing acidocalcisomes. However, in spite of its frequent use in humans, amiodarone use may lead to a number of side effects, due at least in part to the presence of two iodine atoms in its structure, which may contribute, for example, to its thyroid toxicity.…”

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confidence: 77%

“…L. mexicana (Bel 21 strain) promastigotes were cultured in liver infusion-tryptose (LIT) medium supplemented with 10% fetal bovine serum using continuous agitation (100 rpm) at 29°C, as reported previously (8). A growth curve was performed to evaluate the susceptibility of parasites to either dronedarone or amiodarone at different concentrations; live parasites were counted daily using a Neubauer chamber.…”

Section: Methodsmentioning

confidence: 99%

“…L. mexicana promastigotes were loaded with the fluorescent ratiometric indicator fura 2 in order to evaluate the effect of dronedarone on [Ca 2ϩ ] i as reported previously (8). Briefly, 1 ϫ 10 8 parasites were collected by centrifugation at 600 ϫ g for 2 min and washed twice with a loading buffer (137 mM NaCl, 4 mM KCl, 1.5 mM KH 2 Acidocalcisome alkalinization.…”

Section: Methodsmentioning

confidence: 99%

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Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy

Benaím

Casanova

Hernández-Rodríguez

et al. 2014

Antimicrob Agents Chemother

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g Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. They function by disrupting intracellular Ca 2؉ homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against Leishmania mexicana, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of L. mexicana promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with T. cruzi amastigotes (0.65 nM versus 0.75 M). As with amiodarone, dronedarone affects intracellular Ca 2؉ homeostasis in the parasite, inducing an elevation of intracellular Ca 2؉ levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.

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confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy

Benaím

Casanova

Hernández-Rodríguez

et al. 2014

Antimicrob Agents Chemother

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“…This is the case of some drugs that alter the Ca2 þ homeostasis. For instance, one well-characterized drug, mitelfosine, opens an uncharacterized plasma membrane Ca2 þ channel in Leishmania (Benaim et al, 2013). Interestingly, the mechanism of action of some approved antiarrhythmic drugs also is based on altering Ca2 þ homeostasis, and some of them are promising candidates for parasite disease treatment.…”

Section: Drugs and Potential Targetsmentioning

confidence: 99%

“…Efforts are also focused on developing novel drugs by using different strategies, from highthroughput screening for the identification of new targets to the characterization of already marketed drugs that display activity not only against their specific target but also against Leishmania parasites (Benaim et al, 2013(Benaim et al, , 2014De Menezes et al, 2015;Paniz Mondolfi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Nuclear DNA replication and repair in parasites of the genusLeishmania: Exploiting differences to develop innovative therapeutic approaches

Uzcanga

Lara

Gutiérrez

et al. 2016

Critical Reviews in Microbiology

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The emerging paradigm of calcium homeostasis as a new therapeutic target for protozoan parasites

Gupta

Goicoechea

Pearce

et al. 2021

Medicinal Research Reviews

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Calcium channels (CCs), a group of ubiquitously expressed membrane proteins, are involved in many pathophysiological processes of protozoan parasites. Our understanding of CCs in cell signaling, organelle function, cellular homeostasis, and cell cycle control has led to improved insights into their structure and functions. In this article, we discuss CCs characteristics of five major protozoan parasites Plasmodium, Leishmania, Toxoplasma, Trypanosoma, and Cryptosporidium. We provide a comprehensive review of current antiparasitic drugs and the potential of using CCs as new therapeutic targets. Interestingly, previous studies have demonstrated that human CC modulators can kill or sensitize parasites to antiparasitic drugs.Still, none of the parasite CCs, pumps, or transporters has been validated as drug targets. Information for this review draws from extensive data mining of genome sequences, chemical library screenings, and drug design studies. Parasitic resistance to currently approved therapeutics is a serious and emerging threat to both disease control and management efforts. In this article, we suggest that the disruption of calcium homeostasis may be an effective approach to develop new anti-parasite drug candidates and reduce parasite resistance.

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Identification of a sphingosine-sensitive Ca2+ channel in the plasma membrane of Leishmania mexicana

Cited by 25 publications

References 28 publications

Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy

Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy

Nuclear DNA replication and repair in parasites of the genusLeishmania: Exploiting differences to develop innovative therapeutic approaches

The emerging paradigm of calcium homeostasis as a new therapeutic target for protozoan parasites

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