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

Abstract

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 Ca2+-sensitive photoprotein aequorin, we found that oleandrin exposure resulted in Ca2+ influx into the cytosol and that failing to pump Ca2+ from the cytosol to the vacuole increased oleandrin toxicity. We also found that oleandrin exposure induced Mn2+ accumulation by yeast cells via the plasma membrane Smf1 and that mutants with defects in Mn2+ homeostasis are oleandrin-hypersensitive. Our data suggest that combining oleandrin with agents which alter Ca2+ or Mn2+ uptake may be a way of controlling oleandrin toxicity.

Oleandrin: A Systematic Review of its Natural Sources, Structural Properties, Detection Methods, Pharmacokinetics and Toxicology

“…CGs are naturally derived compounds with broad pharmacological activities that show considerable structural diversity. However, they have a common structural motif and generally consist of three structural features: An aglycone-steroidal moiety, a lactone ring with five or six carbons, and a glycosil moiety ( McConkey et al, 2000 ; Ruta et al, 2020 ). The aglycone-steroidal moiety is considered the pharmacophoric moiety responsible for the activity of CGs ( Schonfeld et al, 1985 ).…”

Poisoning by Nerium oleander L. in Franconia Geese

“…Their action is mainly exerted through the inhibition of Na + /K + ATPase, which causes an increase in the sodium and, consequently, calcium concentrations in cardiomyocytes through the action of the sodium-calcium exchanger [8]. More recent studies have also hypothesized the involvement of stretch-activated Ca 2+ permeable cation channels [9]. The increase in the intracellular Ca 2+ concentration induces a positive inotropic effect [10].…”

Isolation and Anti-Yeast Activity of Secondary Metabolites of Soursop Leaf Endophytic Fungi

“…The complete genome sequence is beneficial as a reference for humans and other eukaryotes (Engel et al, 2014). Ruta et al (2020) explained that S. cerevisiae could be manipulated to be a perfect model as a eukaryotic cell for anti-cancer assays. Anti-cancer test using S. cerevisiae was based on the ability of the test compound to inhibit the growth of S. cerevisiae in the growth media.…”