Amiodarone effects on membrane organization evaluated by fluorescence polarization

Antunes-Madeira, Maria do Carmo; Videira, Romeu A.; Klüppel, Ma. Lúcia W.; Madeira, Vítor V. M. C.

doi:10.1016/0167-5273(94)02247-g

Cited by 21 publications

(17 citation statements)

References 23 publications

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“…AMD is an antiarrhythmic drug observed to possess antifungal properties against a wide range of fungi in vitro (9). The mechanism of AMD action has been linked to rapid opening of plasma membrane calcium channels (10, 18, 37), reduced membrane fluid- ity (2,46), and disruption of the cell cycle (53) in C. neoformans and S. cerevisiae. Recently, it was reported that the fungicidal effect of AMD in S. cerevisiae is a consequence of calcium stress involving the calcineurin-responsive transcription factor Crz1p (51,53).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans

Gamarra¹,

Rocha²,

Zhang

et al. 2010

Antimicrob Agents Chemother

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The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In Saccharomyces cerevisiae, its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor CRZ1. In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant Candida albicans. To establish its mechanism of toxicity in C. albicans, we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five C. albicans strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up-or downregulated genes included genes involved in Ca 2؉ homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model.Candida albicans is the most frequently observed opportunistic human fungal pathogen causing mucosal and systemic infections in individuals with compromised immune defenses (44). Antifungal therapy is limited by the paucity of chemical classes, toxicity, drug resistance, moderate response rates, and substantial interpatient variation in serum drug levels. Thus, candidiasis remains a challenging opportunistic infection with high mortality, despite current available treatment. There is a pressing need for alternative treatments with new drug classes representing novel drug targets. One promising new antifungal class is represented by amiodarone (AMD), a drug now in clinical use as an antiarrhythmic. AMD has shown fungicidal activity against yeasts and a range of clinically important fungi, including C. albicans, Cryptococcus neoformans, Fusarium oxysporum, and Aspergillus nidulans (9, 53). In addition, low doses of AMD have been reported to be synergistic with different azoles in itraconazole-resistant A. fumigatus strains (1) and also in the protozoans Trypanosoma cruzi (4) and Leishmania mexicana (49).In Saccharomyces cerevisiae, it is known that AMD affects calcium homeostasis (10), leading to an immediate influx of Ca 2ϩ and a rapid activation of the calcineurin pathway, including nuclear accumulation of the calcineurin-regulated Crz1p. Transcriptional profiling also revealed an apparent disruption of nutrient sensing/signaling within minutes based on the upregulation of ge...

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Section: Discussionmentioning

confidence: 99%

Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans

Gamarra¹,

Rocha²,

Zhang

et al. 2010

Antimicrob Agents Chemother

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“…Mechanistic Insights from Transcriptional Profiling-Amiodarone is a cationic amphiphilic drug that has a strong preference to partition into the membrane bilayer where it has been shown to exert an ordering effect on lipids, resulting in a decrease in membrane fluidity (2,21). In yeast, amiodarone triggers the rapid opening of plasma membrane calcium channels (4,5).…”

Section: Discussionmentioning

confidence: 99%

Global Disruption of Cell Cycle Progression and Nutrient Response by the Antifungal Agent Amiodarone

Zhang

Rao

2007

Journal of Biological Chemistry

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The antiarrhythmic drug amiodarone has fungicidal activity against a broad range of fungi. In Saccharomyces cerevisiae, it elicits an immediate influx of Ca 2؉ followed by mitochondrial fragmentation and eventual cell death. To dissect the mechanism of its toxicity, we assessed the transcriptional response of S. cerevisiae to amiodarone by DNA microarray. Consistent with the drug-induced calcium burst, more than half of the differentially transcribed genes were induced by high levels of CaCl 2 . Amiodarone also caused rapid nuclear accumulation of the calcineurin-regulated Crz1. The majority of genes induced by amiodarone within 10 min were involved in utilization of alternative carbon and nitrogen sources and in mobilizing energy reserves. The similarity to nutrient starvation responses seen in stationary phase cells, rapamycin treatment, and late stages of shift to diauxic conditions and nitrogen depletion suggests that amiodarone may interfere with nutrient sensing and regulatory networks. Transcription of a set of nutrient-responsive genes was affected by amiodarone but not CaCl 2 , indicating that activation of the starvation response was independent of Ca 2؉ . Genes down-regulated by amiodarone were involved in all stages of cell cycle control. A moderate dose of amiodarone temporarily delayed cell cycle progression at G 1 , S, and G 2 /M phases, with the Swe1-mediated delay in G 2 /M phase being most prominent in a calcineurin-dependent manner. Overall, the transcriptional responses to amiodarone revealed by this study were found to be distinct from other classes of antifungals, including the azole drugs, pointing toward a novel target pathway in combating fungal pathogenesis.

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“…This separation of the curves towards higher GP indicates a nonhomogeneous, uncooperative system and that the presence of AMI caused a small ''structuring effect'' on the disordered phase. Similar effect was reported in reference (Antunes-Madeira et al, 1995), where DMPC liposomes containing AMI were studied and its effect was evaluated by fluorescence polarization. Both in reference (Antunes-Madeira et al, 1995) and in this work, an increase in the content of AMI in the liposome affects only the fluid phase of the bilayer but not the gel phase.…”

Section: Biophysical State Of Membranes Of Dmpc Liposomes Containing mentioning

confidence: 59%

“…The zwitterionic lipid dimiristoyl-phosphatidylcholine (DMPC) organized in Langmuir monolayer was used as biomembrane model. At the experimental temperature DMPC monolayers have the ability to organize in a liquid-expanded phase at all surface pressures until collapse (Antunes-Madeira et al, 1995). AMI showed a good ability to penetrate DMPC monolayers (Figure 2b).…”

Section: Resultsmentioning

confidence: 97%

Study of the influence of ascorbyl palmitate and amiodarone in the stability of unilamellar liposomes

Benedini

Antollini

Fanani

et al. 2014

Molecular Membrane Biology

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Amiodarone (AMI) is a low water-solubility drug, which is very useful in the treatment of severe cardiac disease. Its adverse effects are associated with toxicity in different tissues. Several antioxidants have been shown to reduce, and prevent AMI toxicity. The aim of this work was to develop and characterize Dimyristoylphosphatidylcholine (DMPC) liposomal carriers doped with ascorbyl palmitate (Asc16) as antioxidant, in order to either minimize or avoid the adverse effects produced by AMI. The employment of liposomes would avoid the use of cosolvents in AMI formulations, and Asc16 could minimize the adverse effects of AMI. To evaluate the partition and integration of AMI and Asc16 in lipid membranes, penetration studies into DMPC monolayers were carried out. The disturbance of the liposomes membranes was studied by generalized polarization (GP). The stability of liposomes was evaluated experimentally and by means of the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The size particle and zeta potential (ζ) values of the liposomes were used for application in calculations for attractive and repulsive forces in DLVO theory. In experimental conditions all of these vesicles showed stability at time 0, but only DMPC + Asc16 10% + AMI 10% liposomes kept their size stable and ζ during 28 days. These results are encouraging and suggest that such systems could be suitable for AMI delivery formulations.

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Amiodarone effects on membrane organization evaluated by fluorescence polarization

Cited by 21 publications

References 23 publications

Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans

Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans

Global Disruption of Cell Cycle Progression and Nutrient Response by the Antifungal Agent Amiodarone

Study of the influence of ascorbyl palmitate and amiodarone in the stability of unilamellar liposomes

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