| Summary: | Oleandrin, the main component of <i>Nerium oleander</i> L. extracts, is a cardiotoxic glycoside with multiple pharmacological implications, having potential anti-tumoral and antiviral characteristics. Although it is accepted that the main mechanism of oleandrin action is the inhibition of Na<sup>+</sup>/K<sup>+</sup>-ATPases and subsequent increase in cell calcium, many aspects which determine oleandrin cytotoxicity remain elusive. In this study, we used the model <i>Saccharomyces cerevisiae</i> to unravel new elements accounting for oleandrin toxicity. Using cells expressing the Ca<sup>2+</sup>-sensitive photoprotein aequorin, we found that oleandrin exposure resulted in Ca<sup>2+</sup> influx into the cytosol and that failing to pump Ca<sup>2+</sup> from the cytosol to the vacuole increased oleandrin toxicity. We also found that oleandrin exposure induced Mn<sup>2+</sup> accumulation by yeast cells via the plasma membrane Smf1 and that mutants with defects in Mn<sup>2+</sup> homeostasis are oleandrin-hypersensitive. Our data suggest that combining oleandrin with agents which alter Ca<sup>2+</sup> or Mn<sup>2+</sup> uptake may be a way of controlling oleandrin toxicity.
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