Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces cerevisiae Cells

Oleandrin, the main component of Nerium oleander 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(+)/K(+)-ATPases and subsequent increase in cell calcium, many aspects which determine oleandrin cytotoxicity remain elusive. In this study, we used the model Saccharomyces cerevisiae to unravel new elements accounting for oleandrin toxicity. Using cells expressing the Ca(2+)-sensitive photoprotein aequorin, we found that oleandrin exposure resulted in Ca(2+) influx into the cytosol and that failing to pump Ca(2+) from the cytosol to the vacuole increased oleandrin toxicity. We also found that oleandrin exposure induced Mn(2+) accumulation by yeast cells via the plasma membrane Smf1 and that mutants with defects in Mn(2+) homeostasis are oleandrin-hypersensitive. Our data suggest that combining oleandrin with agents which alter Ca(2+) or Mn(2+) uptake may be a way of controlling oleandrin toxicity.