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

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Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces Cerevisiae Cells molecules Article Cytotoxicity of Oleandrin Is Mediated by Calcium Influx and by Increased Manganese Uptake in Saccharomyces cerevisiae Cells Lavinia L. Ruta , Claudia V. Popa and Ileana C. Farcasanu * Department of Organic Chemistry, Biochemistry and Catalysis, Faculty of Chemistry, University of Bucharest, Sos. Panduri 90-92, 050663 Bucharest, Romania; [email protected] (L.L.R.); [email protected] (C.V.P.) * Correspondence: [email protected]; Tel.: +40-721-067-169 Academic Editors: Luisa Tesoriere and Alessandro Attanzio Received: 17 August 2020; Accepted: 15 September 2020; Published: 17 September 2020 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. Keywords: oleandrin; Saccharomyces cerevisiae; calcium; manganese 1. Introduction Nerium oleander L., commonly known as oleander, is an ornamental shrub with both pharmacological and toxicological properties, whose parts have been used in ethnomedicine since ancient times as natural remedies against cardiac illnesses, cancer, diabetes, asthma, skin diseases, inflammation, etc. [1]. Oleander extracts need to be regarded with caution as they are poisonous in high doses, having important cardiotoxic effects [2–4]. Nevertheless, many of the individual components of oleander extracts have been found to have anti-tumor, anti-proliferative, anti-inflammatory and even antiviral properties [5–8]. One of the emblematic components of oleander extracts is oleandrin (PubChem CID 11541511), a cardiotonic glycoside similar in toxicity and structure to digitoxin from Digitalis purpurea L. [7]. Oleandrin (Figure1a) is a lipid-soluble glycoside comprised of oleandrigenin (the steroid aglycone) and D-diginosyl (a sugar-like moiety) which slightly increases oleandrin’s water solubility, which otherwise is very low [9]. Oleandrin is mainly responsible for the toxicity of oleander sap and, just as with digitoxin, it is thought to act as a cardiotonic by inhibiting the sodium and potassium ATPases (Na+/K+-ATPase) and subsequently increasing Ca2+ concentration, resulting in activation of various cell survival and death pathways [10,11]. In spite of its toxicity, oleandrin has been increasingly investigated as several studies indicated its potential as an anticancer [12–16] as well as antiviral drug [8,17–19]. The therapeutic potential of oleandrin is hampered by its cytotoxicity and by the fact that although several signaling cascades targeted by oleandrin through inhibition of Na+/K+-ATPase have been identified [20], and that it is considered that oleandrin may cause destruction Molecules 2020, 25, 4259; doi:10.3390/molecules25184259 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 15 Molecules 2020, 25, 4259 2 of 14 cascades targeted by oleandrin through inhibition of Na+/K+-ATPase have been identified [20], and ofthat tumor it is considered cells by inducing that oleandrin oxidative may stress cause through destruction generation of tumor or reactive cells by oxygen inducing species oxidative (ROS) stress [21], manythrough aspects generation which or mediate reactive oleandrin oxygen toxicityspecies still(ROS) remain [21], obscure.many aspects which mediate oleandrin toxicity still remain obscure. (a) (b) (c) Figure 1. Effect of oleandrin on yeast growth. (a) Oleandrin structure. (b)Effect of oleandrin Figure 1. Effect of oleandrin on yeast growth. (a) Oleandrin structure. (b) Effect of oleandrin concentration on growth of wild type cells. BY4741 cells were inoculated (OD600 = 0.05) and grown inconcentration SD (synthetic on dextrose)growth of liquidwild type medium cells. BY4741 in the presence cells were of inoculated various concentrations (OD600 = 0.05) and of oleandrin. grown in SD (synthetic dextrose) liquid medium in the presence of various concentrations of oleandrin. Cell Cell density was determined spectrophotometrically at 600 nm (OD600) as described in the Materials anddensity Methods was determinedsection. One-way spectrophotometrically ANOVA, * p < at0.05; 600 nm ** p (OD< 0.01;600) as *** describedp < 0.005. in the (c )Materials Growth and on oleandrin-supplementedMethods section. One-way solid ANOVA, medium. *p Wild < 0.05; type ** (WT)p < 0.01; or knockout ***p < mutant0.005. (c cells) Growthcch1D, mid1on oleandrinD, pmc1D-, smf1supplementedD, pmr1D andsolidahp1 medium.D with Wild oleandrin type (WT) sensitivity or knockout different mutant from cells WT cch1Δ (see Table, mid1Δ S1), pmc1Δ were, serially smf1Δ, dilutedpmr1Δ and and ahp1Δ stamped with on oleandrin SD/agar containing sensitivity ordifferent not 100 from ng/mL WT oleandrin. (see Table Plates S1) were were serially photographed diluted and stamped on SD/agar containing or not 100 ng/mL oleandrin. Plates were photographed after 3 after 3 days’ incubation at 30 ◦C. days’ incubation at 30 °C. In this study, we made use of the model microorganism Saccharomyces cerevisiae to investigate oleandrinIn this toxicity study on, we yeast made cells. useS. of cerevisiae the modelis a simplifiedmicroorganism model Saccharomyces of the eukaryotic cerevisiae cell used to toinvestigate elucidate manyoleandrin of the toxicity molecular on yeast mechanisms cells. S. conserved cerevisiae is in a higher simplified eukaryotes model due of tothe the eukaryotic ease of manipulation, cell used to tractableelucidate genetics, many of exhaustive the molecular genome mechanisms annotation conserved and less restrictive in higher ethical eukaryotes constraints due [to22 –the24]. ease So far,of nomanipulation, study concerning tractable the egenetics,ffect of oleander exhaustive extracts genome or oleandrin annotation has beenand reportedless restrictive in S. cerevisiae ethical. Asconstraints oleandrin [2 was2–24 shown]. So far, to alterno study the fluidity concerning of the the human effect cell of membraneoleander extracts [25], we or hypothesized oleandrin has that been the primaryreported interaction in S. cerevisiae between. As o oleandrinleandrin andwas theshown yeast to cells alter would the fluidity occur atof the the plasma human membrane cell membrane level. We[25] therefore, we hypothesized tested the that oleandrin the primary toxicity interaction on S. cerevisiae betweenmutants oleandri withn and defects the yeast in the cells cell would membrane occur transportat the plasma of monovalent membrane ionslevel. (Na We+ thereforeand K+), Catested2+ or the essential oleandrin metal toxicity ions. on S. cerevisiae mutants with defectsIn inS. the cerevisiae cell membrane, the movement transport of of Na monovalent+ and K+ acrossions (Na the+ and plasma K+), Ca membrane2+ or essential isensured metal ions by. Ena1In P-type S. cerevisiae Na+/H, +theATPase, movement Nha1 ofNa Na++/ Hand+ antiporter, K+ across the outward-rectifier plasma membrane K+ channelis ensured Tok1 by andEna1 the P- Trk1p–Trk2ptype Na+/H+ potassiumATPase, Nha1 transport Na+/H system+ antiporter, [26]. Regulation outward-rectifier of these K transporters+ channel Tok1 has beenand extensivelythe Trk1p– Trk2p potassium transport system [26]. Regulation of these transporters has been extensively Molecules 2020, 25, 4259 3 of 14 reviewed [26] and it was shown that salt stress and alkaline stress induce calcium-mediated responses 2+ 2+ 2+ by generating Ca flux into the cytosol [27,28]. Abrupt increases in the cytosolic Ca ([Ca ]cyt) represent a universal mechanism to trigger signaling cascades involved in cell adaptation, survival or 2+ 2+ death [29]. In S. cerevisiae, the increase in [Ca ]cyt occurs through Ca entry into the cytosol via the Cch1/Mid1 channel situated at the plasma membrane [27,30] or via the vacuolar transient receptor potential channel TRPY1 (formerly known as Yvc1) [31–33]. Cch1 is similar to the pore-forming subunit (α1) of the plasma membrane, and voltage-gated Ca2+ channels (VGCC) from higher eukaryotes, including humans [34]. Cch1 interacts and partially co-localizes with Mid1p, a stretch-activated cation channel which resembles the VGCC α2/δ regulatory subunits and Na+ leak channel non-selective 2+ (NALCN)-associated proteins [35]. Prolonged high [Ca ]cyt is detrimental to cells, therefore the 2+ 2+ normal very low [Ca ]cyt must be restored through the action of Ca pumps and exchangers [33]. In S. cerevisiae, this is done by the concerted actions of the vacuolar Ca2+-ATPase Pmc1 (similar to mammalian PMCA1a) [36] and of the vacuolar Ca2+/H+ exchanger Vcx1 [37,38] (which independently 2+ 2+ 2+ transport [Ca ]cyt into the vacuole) and by the secretory Ca -ATPase Pmr1, which
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