Amiodarone Destabilizes Intracellular Ca ²⁺ Homeostasis and Biosynthesis of Sterols in Leishmania mexicana

Abstract

. Here we show that at therapeutic concentrations, amiodarone has a profound effect on the viability of Leishmania mexicana promastigotes. Additionally, its effect on the viability of the parasite was greater against intracellular amastigotes than against promastigotes, and it did not affect the host cell. Using fluorimetric and confocal microscopy techniques, we also demonstrated that the mechanism of action of amiodarone was related to the disruption of intracellular Ca 2؉ homeostasis through a direct action not only on the mitochondria but also on the acidocalcisomes. On the other hand, analysis of the free sterols in promastigotes incubated with amiodarone showed that this drug also affected the biosynthesis of 5-dehydroepisterol, which results in squalene accumulation, thus suggesting that amiodarone inhibits the squalene epoxidase activity of the parasite. Taken together, the results obtained in the present work point to a more general effect of amiodarone in trypanosomatids, opening potential therapeutic possibilities for this infectious disease.

Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109

“…Similar results were obtained with amiodarone and dronedarone in T. cruzi and L. mexicana (1)(2)(3)(4)(5). Here, as shown in Fig.…”

“…In the presence of 2 mM external Ca 2ϩ , the same amount of Ca 2ϩ is released by SQ109 (as determined using fura 2) as in the absence of external Ca 2ϩ (i.e., in the presence of 8 mM ethylene glycol tetraacetic acid [EGTA], a highaffinity Ca 2ϩ -specific chelator), which means that it is not the external Ca 2ϩ that is involved in the increase in Ca 2ϩ i . Rather, Ca 2ϩ is released from internal stores, mitochondria and acidocalcisomes, again, just as found for T. cruzi and L. mexicana with amiodarone and dronedarone (1)(2)(3)(4)(5). This disruption of Ca 2ϩ homeostasis in addition to the effects on the proton motive force (as seen also in mycobacteria [10][11][12]) are likely to make major contributions to L. mexicana cell killing.…”

“…In previous work (1)(2)(3)(4)(5), we discovered that the antiarrhythmia drugs amiodarone (Fig. 1, compound 1) and dronedarone ( Fig.…”

Pharmacokinetics of Sulfadoxine and Pyrimethamine for Intermittent Preventive Treatment of Malaria During Pregnancy and After Delivery

“…Previous reports generally show that sulfadoxine concentrations are lower in pregnant women when compared to nonpregnant adults and are inconsistent for pyrimethamine 5, 14, 15…”

SQ109, a New Drug Lead for Chagas Disease

“…Similar results were later found with Leishmania spp. (8,9), and amiodarone is now used clinically for the treatment of chronic Chagas disease (10) and disseminated cutaneous leishmaniasis (11), as discussed in a recent review (12).…”