Induction of interleukin-1β, tumour necrosis factor-α and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan

Falk, Rama; Hacham, Moshe; Nyska, Abraham; Foley, Julie F.; Domb, Abraham J.; Polacheck, Itzhack

doi:10.1093/jac/dki090

Cited by 21 publications

(20 citation statements)

References 56 publications

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“…The protective effect exerted by pentoxifylline against cisplatin nephrotoxicity [140] and the lower ability to induce apoptosis for amphotericin B-arabinoglycan as compared to amphotericin B-deoxycholate [141] could result from inhibition of TNF-a production and ensuing dampening of death receptor signalling.…”

Section: Modulation Of Major Apoptosis Pathwaysmentioning

confidence: 99%

Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation

et al. 2007

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Apoptosis plays a central role not only in the physiological processes of kidney growth and remodeling, but also in various human renal diseases and drug-induced nephrotoxicity. We present in a synthetic fashion the main molecular and cellular pathways leading to drug-induced apoptosis in kidney and the mechanisms regulating it. We illustrate them using three main nephrotoxic drugs (cisplatin, gentamicin, and cyclosporine A). We discuss the main regulators and effectors that have emerged as key targets for the design of therapeutic strategies. Novel approaches using gene therapy, antisense strategies, recombinant proteins, or compounds obtained from both classical organic and combinatorial chemistry are examined. Finally, key issues that need to be addressed for the success of apoptosis-based therapies are underlined.

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Section: Modulation Of Major Apoptosis Pathwaysmentioning

confidence: 99%

Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation

et al. 2007

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“…AMB-related toxicity is associated with the inductions of interleukin 1␤ (IL-1␤), tumor necrosis factor ␣ (TNF-␣), and apoptosis in organs. These effects were not observed with the AMB-AG conjugate (AMB-AGC), suggesting its potential as a safer formulation for therapeutic use (19). AG is an inexpensive natural product, and the conjugation reactions are performed at room temperature, revealing promise for a potentially low-cost drug.…”

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confidence: 99%

Toxicity Mechanisms of Amphotericin B and Its Neutralization by Conjugation with Arabinogalactan

Kagan

Ickowicz

Shmuel

et al. 2012

Antimicrob Agents Chemother

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c 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. Opportunistic fungal infections have emerged as an important cause of morbidity and mortality in immunodeficient patients (34). Amphotericin B (AMB) is considered one of the most effective antifungal agents; it exhibits wide-spectrum activity against both filamentous and yeast-like fungi, its pharmacokinetic and pharmacodynamic profiles are superior to those of other antifungal agents, and it is fungicidal, in contrast to most azoles which are fungistatic (3,39,53). The fungicidal effect is important, since most patients suffering from invasive fungal infections are immunocompromised (34). However, the infusionrelated and cumulative toxicities, particularly nephrotoxicity (14,20,30), of AMB have resulted in reductions in the routine use of deoxycholate micellar AMB formulations and the development of less-toxic high-cost lipid AMB formulations (16,36). To develop a soluble, less-toxic, and less costly formulation, AMB has been conjugated with various soluble macromolecules (18,37,(47)(48)(49).We conjugated AMB with arabinogalactan (AG) (18), which significantly increased the water solubility of AMB, reduced its toxicity, and resulted in an efficacy similar to that of Fungizone (a deoxycholate micellar formulation) and AmBisome (a lipid-based formulation) (18). AMB-related toxicity is associated with the inductions of interleukin 1␤ (IL-1␤), tumor necrosis factor ␣ (TNF-␣), and apoptosis in organs. These effects were not observed with the AMB-AG conjugate (AMB-AGC), suggesting its potential as a safer formulation for therapeutic use (19). AG is an inexpensive natural product, and the conjugation reactions are performed at room temperature, revealing promise for a potentially low-cost drug. AMB penetrates the plasma membrane (PM) and interacts with its sterols to form transmembrane channels, resulting in the leakage of monovalent ions and metabolites, which leads to cell death (5,22,4...

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“…118 The conjugate was found to be active against leismania 119,120 , and others parasites. 121,122 Folic acid and methotrexate (MTX) were conjugated to AG (AG-folic acid-MTX). This conjugate can differentially deliver a cytotoxic cargo to cells over expressing folate receptors.…”

Section: Conjugates Using Arabinogalactan Dextran and Pullulanmentioning

confidence: 99%

Polysaccharide-Based Conjugates for Biomedical Applications

et al. 2015

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Polysaccharides contain different functional groups (such as hydroxyl, amino, carboxylic acid, aldehydes) that make them ideal for conjugation. They are biodegradable, biocompatible, and hydrophilic. Polysaccharide conjugates have been used in drug, gene, and macromolecule delivery, tissue engineering, and other biomedical applications. Polysaccharide conjugates have also been used primarily for solubilization and controlled release of hydrophobic moieties. The advent of nanotechnology, gene therapy, and tissue engineering influenced the way these conjugates are now used. Modern day conjugates are modulated to be thermoresponsive, pH-responsive, photoresponsive, or target-specific (receptor mediated targeting). This Review briefly introduces different polysaccharides followed by different synthetic strategies used for conjugation; finally, recent applications were compiled.

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Induction of interleukin-1β, tumour necrosis factor-α and apoptosis in mouse organs by amphotericin B is neutralized by conjugation with arabinogalactan

Abstract: AMB-related toxicity is associated with induction of IL-1beta, TNF-alpha and apoptosis in organs. These effects were not observed with AMB-AG conjugate, suggesting its potential as a safer formulation for therapy.

Cited by 21 publications

References 56 publications

Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation

Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation

Toxicity Mechanisms of Amphotericin B and Its Neutralization by Conjugation with Arabinogalactan

Polysaccharide-Based Conjugates for Biomedical Applications

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