Journal Article

Bumetanide annihilation of amphotericin B-induced apoptosis and cytotoxicity is due to its effect on cellular K<sup>+</sup> flux

L. Marklund, P. Behnam-Motlagh, R. Henriksson and K. Grankvist

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 48, issue 6, pages 781-786
Published in print December 2001 | ISSN: 0305-7453
Published online December 2001 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/48.6.781
Bumetanide annihilation of amphotericin B-induced apoptosis and cytotoxicity is due to its effect on cellular K+ flux

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The antifungal antibiotic amphotericin B causes considerable toxic effects during clinical therapy. We have shown previously that amphotericin B-induced cytotoxicity and apoptosis were eradicated by the Na+, K+, 2Cl cotransport inhibitor bumetanide. To elucidate the role of K+ flux and the activity of Na+, K+ ATPase and Na+, K+, 2Cl cotransport in apoptosis and cytotoxicity induced by amphotericin B alone and combined with bumetanide, we quantified the influx and efflux of K+ of mesothelioma cells (P31) using the K+ analogue 86Rb+ with ouabain (100 μmol/L) as the K+ influx probe. To determine the susceptibility of Candida albicans to amphotericin B when combined with bumetanide we used a plate diffusion method. Amphotericin B or bumetanide alone significantly stimulated 86Rb+ efflux during the first 15 min. However, when added simultaneously, the cellular 86Rb+ efflux was markedly decreased. Amphotericin B (3 mg/L) had no effect on immediate (15 min) total 86Rb+ influx. When bumetanide (100 μmol/L) was added, the total 86Rb+ influx was markedly reduced due to inhibition of augmented Na+, K+, 2Cl cotransport and low Na+, K+ ATPase activity. Bumetanide did not affect the susceptibility of C. albicans to amphotericin B, which suggests that bumetanide or related drugs could be used in antifungal therapy to increase amphotericin B effectiveness without increasing its adverse effects. We suggest that bumetanide hampering of amphotericin B-induced cytotoxicity and apoptosis could be due to an immediate reduction of cellular K+ efflux as well as disordered K+ influx.

Journal Article.  3585 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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