Journal of Antimicrobial Chemotherapy (2001) 48, 781-786
© 2001 The British Society for Antimicrobial Chemotherapy
Bumetanide annihilation of amphotericin B-induced apoptosis and cytotoxicity is due to its effect on cellular K+ flux
a Departments of Clinical Chemistry and b Oncology, Umeå University, S-901 87 Umeå, Sweden
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.
* Corresponding author. Tel/Fax: +46-90-785-12-62; E-mail: kjell.Grankvist{at}klinkemi.umu.se
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