Role of Calcium in Trypanocidal Drug Action

Clarkson, Allen B.; Amole, Babatunde O.

doi:10.1126/science.6805075

Cited by 25 publications

(4 citation statements)

References 11 publications

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“…A role for Ca 2+ in the action of some anti-parasitic drugs has long been appreciated [92] and many anti-parasitic drugs that are known to affect mammalian Ca 2+ channels have effects on Ca 2+ signalling in parasites. For example, amiodarone [93], nimodipine [94] and several other 1,4-dihydropyridines [95], as well as a range of Ca 2+ channel and calmodulin antagonists [96] may exert anti-parasitic effects via disruption of Ca 2+ homeostasis in parasites.…”

Section: Discussionmentioning

confidence: 99%

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

2011

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Ca2+ channels regulate many crucial processes within cells and their abnormal activity can be damaging to cell survival, suggesting that they might represent attractive therapeutic targets in pathogenic organisms. Parasitic diseases such as malaria, leishmaniasis, trypanosomiasis and schistosomiasis are responsible for millions of deaths each year worldwide. The genomes of many pathogenic parasites have recently been sequenced, opening the way for rational design of targeted therapies. We analyzed genomes of pathogenic protozoan parasites as well as the genome of Schistosoma mansoni, and show the existence within them of genes encoding homologues of mammalian intracellular Ca2+ release channels: inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), two-pore Ca2+ channels (TPCs) and intracellular transient receptor potential (Trp) channels. The genomes of Trypanosoma, Leishmania and S. mansoni parasites encode IP3R/RyR and Trp channel homologues, and that of S. mansoni additionally encodes a TPC homologue. In contrast, apicomplexan parasites lack genes encoding IP3R/RyR homologues and possess only genes encoding TPC and Trp channel homologues (Toxoplasma gondii) or Trp channel homologues alone. The genomes of parasites also encode homologues of mammalian Ca2+ influx channels, including voltage-gated Ca2+ channels and plasma membrane Trp channels. The genome of S. mansoni also encodes Orai Ca2+ channel and STIM Ca2+ sensor homologues, suggesting that store-operated Ca2+ entry may occur in this parasite. Many anti-parasitic agents alter parasite Ca2+ homeostasis and some are known modulators of mammalian Ca2+ channels, suggesting that parasite Ca2+ channel homologues might be the targets of some current anti-parasitic drugs. Differences between human and parasite Ca2+ channels suggest that pathogen-specific targeting of these channels may be an attractive therapeutic prospect.

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Section: Discussionmentioning

confidence: 99%

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

2011

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“…In addition, different treatments with distinct drugs are potentiated in the presence of Ca 2+ . For example, the effect of melarsoprol and also the combination of salicylhidroxamic acid with glycerol on African trypanosomiasis is significantly augmented when Ca 2+ is present (Clarkson and Amole, 1982). Similarly, Ergosterone-coupled Triazol molecules trigger mitochondrial dysfunction, oxidative stress, and acidocalcisomal Ca 2+ release in Leishmania mexicana (Figarella et al, 2015).…”

Section: Targeting Intracellular Ca 2+ Homeostasis As a Strategy Agaimentioning

confidence: 99%

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Benaím

Paniz‐Mondolfi

Sordillo

et al. 2020

Front. Cell. Infect. Microbiol.

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There is no effective cure for Chagas disease, which is caused by infection with the arthropod-borne parasite, Trypanosoma cruzi. In the search for new drugs to treat Chagas disease, potential therapeutic targets have been identified by exploiting the differences between the mechanisms involved in intracellular Ca 2+ homeostasis, both in humans and in trypanosomatids. In the trypanosomatid, intracellular Ca 2+ regulation requires the concerted action of three intracellular organelles, the endoplasmic reticulum, the single unique mitochondrion, and the acidocalcisomes. The single unique mitochondrion and the acidocalcisomes also play central roles in parasite bioenergetics. At the parasite plasma membrane, a Ca 2+-− ATPase (PMCA) with significant differences from its human counterpart is responsible for Ca 2+ extrusion; a distinctive sphingosine-activated Ca 2+ channel controls Ca 2+ entrance to the parasite interior. Several potential anti-trypansosomatid drugs have been demonstrated to modulate one or more of these mechanisms for Ca 2+ regulation. The antiarrhythmic agent amiodarone and its derivatives have been shown to exert trypanocidal effects through the disruption of parasite Ca 2+ homeostasis. Similarly, the amiodarone-derivative dronedarone disrupts Ca 2+ homeostasis in T. cruzi epimastigotes, collapsing the mitochondrial membrane potential (Ψ m), and inducing a large increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i) from this organelle and from the acidocalcisomes in the parasite cytoplasm. The same general mechanism has been demonstrated for SQ109, a new anti-tuberculosis drug with potent trypanocidal effect. Miltefosine similarly induces a large increase in the [Ca 2+ ] i acting on the sphingosine-activated Ca 2+ channel, the mitochondrion and acidocalcisomes. These examples, in conjunction with other evidence we review herein, strongly support targeting Ca 2+ homeostasis as a strategy against Chagas disease.

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“…All members of the genus Trypanosoma are parasites, and trypanosomes of the brucei group produce lethal infections in humans and livestock throughout sub-Saharan Africa. Indirect lines of evidence implicate Ca# + as an important component in the control of trypanosome infections : for example, Ca# + has been shown to potentiate the lethal effects of trypanocidal agents such as Melarsoprol [2], SHAM [2] and HDL [3]. Antagonists of Ca# + -binding proteins are also lethal to trypanosomes [4,5].…”

Section: Introductionmentioning

confidence: 99%

Calcium entry in Trypanosoma brucei is regulated by phospholipase A2 and arachidonic acid

Eintracht

Maathai

Mellors

et al. 1998

Biochemical Journal

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In contrast with mammalian cells, little is known about the control of Ca2+ entry into primitive protozoans. Here we report that Ca2+ influx in pathogenic Trypanosoma brucei can be regulated by phospholipase A2 (PLA2) and the subsequent release of arachidonic acid (AA). Several PLA2 inhibitors blocked Ca2+ entry; 3-(4-octadecyl)-benzoylacrylic acid (OBAA; IC50 0.4+/-0.1 microM) was the most potent. We identified in live trypanosomes PLA2 activity that was sensitive to OBAA and could be stimulated by Ca2+, suggesting the presence of positive feedback control. The cell-associated PLA2 activity was able to release [14C]AA from labelled phospholipid substrates. Exogenous AA (5-50 microM) also initiated Ca2+ entry in a manner that was inhibited by the Ca2+ antagonist La3+ (100 microM). Ca2+ entry did not depend on AA metabolism or protein kinase activation. The cell response was specific for AA, and fatty acids with greater saturation than tetraeicosanoic acid (AA) or with chain lengths less than C20 exhibited greatly diminished ability to initiate Ca2+ influx. Myristate and palmitate inhibited PLA2 activity and also inhibited Ca2+ influx. Overall, these results demonstrate that Ca2+ entry into T. brucei can result from phospholipid hydrolysis and the release of eicosanoic acids.

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Role of Calcium in Trypanocidal Drug Action

Cited by 25 publications

References 11 publications

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Calcium entry in Trypanosoma brucei is regulated by phospholipase A2 and arachidonic acid

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