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Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan
Year:
2012
Authors :
Sionov, Edward
;
.
Volume :
56
Co-Authors:
Kagan, S., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Ickowicz, D., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Shmuel, M., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Altschuler, Y., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Sionov, E., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
Pitusi, M., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Weiss, A., Bio-Imaging Unit, Silverman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
Farber, S., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Domb, A.J., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Polacheck, I., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Facilitators :
From page:
5603
To page:
5611
(
Total pages:
9
)
Abstract:
Amphotericin B (AMB) is an effective antifungal agent. However, its therapeutic use is hampered by its toxicity, mainly due to channel formation across kidney cell membranes and the disruption of postendocytic trafficking. We previously described a safe injectable AMB-arabinogalactan (AG) conjugate with neutralized toxicity. Here we studied the mechanism of the toxicity of free AMB and its neutralization by conjugation with AG. AMB treatment of a kidney cell line modulated the trafficking of three receptors (C-X-C chemokine receptor type 4 [CXCR4], M1 receptor, and human transferrin receptor [hTfnR]) due to an increase in endosomal pH. Similar data were also obtained in yeast but with an increase in vacuolar pH and the perturbation of Hxt2-green fluorescent protein (GFP) trafficking. The conjugation of AMB with AG neutralized all elements of the toxic activity of AMB in mammalian but not in fungal cells. Based on these results, we provide an explanation of how the conjugation of AMB with AG neutralizes its toxicity in mammalian cells and add to the knowledge of the mechanism of action of free AMB in both fungal and mammalian cells. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Note:
Related Files :
amphotericin B
animal cell
Animals
arabinogalactan
Dogs
Galactans
kidney cell
pH
transferrin
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More details
DOI :
10.1128/AAC.00612-12
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
21879
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:47
Scientific Publication
Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan
56
Kagan, S., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Ickowicz, D., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Shmuel, M., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Altschuler, Y., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Sionov, E., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
Pitusi, M., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Weiss, A., Bio-Imaging Unit, Silverman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
Farber, S., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Domb, A.J., Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel
Polacheck, I., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan
Amphotericin B (AMB) is an effective antifungal agent. However, its therapeutic use is hampered by its toxicity, mainly due to channel formation across kidney cell membranes and the disruption of postendocytic trafficking. We previously described a safe injectable AMB-arabinogalactan (AG) conjugate with neutralized toxicity. Here we studied the mechanism of the toxicity of free AMB and its neutralization by conjugation with AG. AMB treatment of a kidney cell line modulated the trafficking of three receptors (C-X-C chemokine receptor type 4 [CXCR4], M1 receptor, and human transferrin receptor [hTfnR]) due to an increase in endosomal pH. Similar data were also obtained in yeast but with an increase in vacuolar pH and the perturbation of Hxt2-green fluorescent protein (GFP) trafficking. The conjugation of AMB with AG neutralized all elements of the toxic activity of AMB in mammalian but not in fungal cells. Based on these results, we provide an explanation of how the conjugation of AMB with AG neutralizes its toxicity in mammalian cells and add to the knowledge of the mechanism of action of free AMB in both fungal and mammalian cells. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Scientific Publication
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