21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions

Rocha, Sayonarah C.; Pessôa, Marco Túlio C.; Neves, Luiza D.R.; Alves, Silmara L.G.; Silva, Luciana M.; Santos, Herica L.; Oliveira, Soraya M.F.; Taranto, Alex Gutterres; Comar, Moacyr; Gomes, Isabella V.; Santos, Fábio V.; Paixão, Natasha; Quintas, Luis Eduardo M.; Noël, François; Pereira, Antonio F.; Tessis, Ana Claudia; Gomes, N.; Moreira, Otacílio C.; Rincón-Heredia, Ruth; Varotti, Fernando P.; Blanco, Gustavo; Villar, José Augusto Ferreira Perez; Contreras, Rubén G.; Barbosa, Leandro A.

doi:10.1371/journal.pone.0108776

Cited by 33 publications

(29 citation statements)

References 110 publications

(112 reference statements)

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“…21-BD, considered the template compound, and the only molecule from this group, did not significantly affect the activity of NKA α2 and α3 isoforms ( Figure S1(A) ). Previous studies from our group have demonstrated that 21-BD inhibits the NKA activity derived from a mouse kidney membrane preparation, which only contains the NKA α1 isoform; and has no effect on rat brain NKA, which mainly expresses the NKA α2 and α3 isoforms 18 .…”

Section: Resultsmentioning

confidence: 80%

“…We have generated a series of compounds by modifying the lactone ring of the CTS digoxin. One of these synthetic digoxin analogues, 21-benzylidene digoxin (21-BD), presented cytotoxic and antiproliferative effects when used on HeLa cancer cells, via inducing apoptosis in those cells, but inhibiting NKA activity just at high micromolar levels 18 , 19 . Subsequently, starting with the structure of digoxin, we synthesised a series of γ-benzylidene derivatives and showed that they have cytotoxic effects on HeLa and RKO cancer cell lines that are independent from the modulation of NKA activity 20 .…”

Section: Introductionmentioning

confidence: 99%

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Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

Pessôa

Alves

Taranto

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA α2 activity, BD-5 inhibiting NKA α1 and NKA α3, BD-10 reducing NKA α1, but stimulating NKA α2 and α3; and BD-14, BD-15, and BD-16 enhancing NKA α3 activity. A molecular-docking approach favoured NKA isoform specific interactions for the compounds that supported their observed activity. These results show that BD compounds are a new type of CTS with the capacity to target NKA activity in an isoform-specific manner.

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Section: Resultsmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

Pessôa

Alves

Taranto

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…45 A recent study conducted by our research group using the cardiotonic steroid 21-BD showed an augment in Na,K-ATPase levels in canine renal cells (MDCK). 46 Thus, an increased Na,K-ATPase expression in digoxintreated N2a cells ( Figure 6) might be closely associated with the increase of the activity of Na,K-ATPase ( Figure 4). We also evaluated whether N2a cells treated with steroids alone would have any change in enzyme expression.…”

Section: Discussionmentioning

confidence: 85%

Evaluation of neuroprotective activity of digoxin and semisynthetic derivatives against partial chemical ischemia

Gonçalves

Valadares

Alves

et al. 2019

J of Cellular Biochemistry

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Recently, cardiotonic steroids (CTS) have been shown to lead to the activation of Na,K‐ATPase at low concentrations in brain, promoting neuroprotection against ischemia. We report here the results of the use of digoxin and its semisynthetic derivatives BD‐14, BD‐15, and BD‐16 against partial chemical ischemic induction followed by reperfusion in murine neuroblastoma cells neuro‐2a (N2a). For chemical ischemic induction, sodium azide (5 mM) was used for 5 hours, and then reperfusion was induced for 24 hours. Na,K‐ATPase activity and protein levels were analyzed in membrane preparation of N2a cells pretreated with the compounds (150 nM), in the controls and in induced chemical ischemia. In the Na,K‐ATPase activity and protein levels assays, the steroids digoxin and BD‐15 demonstrated a capacity to modulate the activity of the enzyme directly, increasing its levels of expression and activity. Oxidative parameters, such as superoxide dismutase (SOD) activity, lipid peroxidation (thiobarbituric acid reactive substance), glutathione peroxidase (GPx), glutathione (GSH) levels, hydrogen peroxide content, and the amount of free radicals (reactive oxygen species) during induced chemical ischemia were also evaluated. Regarding the redox state, lipid peroxidation, hydrogen peroxide content, and GPx activity, we have observed an increase in the chemical ischemic group, and a reduction in the groups treated with CTS. SOD activity increased in all treated groups when compared to control and GSH levels decreased when treated with sodium azide and did not change with CTS treatments. Regarding the lipid profile, we saw a decrease in the content of phospholipids and cholesterol in the chemical ischemic group, and an increase in the groups treated with CTS. In conclusion, the compounds used in this study demonstrate promising results, since they appear to promote neuroprotection in cells exposed to chemical ischemia.

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“…/K ? -ATPase activity of cardiotonic steroids on cell membrane preparations and intact cells (Oselkin et al 2010;Rocha et al 2014). In intact cells, we have complex modulators of the Na ?…”

Section: Discussionmentioning

confidence: 99%

The Influence of Fatty Acid Methyl Esters (FAMEs) in the Biochemistry and the Na+/K+-ATPase Activity of Culex quinquefasciatus Larvae

et al. 2016

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Culex quinquefasciatus is the main vector of lymphatic filariasis and combating this insect is of great importance to public health. There are reports of insects that are resistant to the products currently used to control this vector, and therefore, the search for new products has increased. In the present study, we have evaluated the effects of fatty acid methyl esters (FAMEs) that showed larvicidal activity against C. quinquefasciatus, on glucose, total protein, and triacylglycerol contents and Na(+)/K(+)-ATPase activity in mosquito larvae. The exposure of the fourth instar larvae to the compounds caused a decrease in the total protein content and an increase in the activity of the Na(+)/K(+)-ATPase. Furthermore, the direct effect of FAMEs on cell membrane was assessed on purified pig kidney Na(+)/K(+)-ATPase membranes, erythrocyte ghost membranes, and larvae membrane preparation. No modifications on total phospholipids and cholesterol content were found after FAMEs 20 min treatment on larvae membrane preparation, but only 360 µg/mL FAME 2 was able to decrease total phospholipid of erythrocyte ghost membrane. Moreover, only 60 and 360 µg/mL FAME 3 caused an activation of purified Na(+)/K(+)-ATPase, that was an opposite effect of FAMEs treatment in larvae membrane preparation, and caused an inhibition of the pump activity. These data together suggest that maybe FAMEs can modulate the Na(+)/K(+)-ATPase on intact larvae for such mechanisms and not for a direct effect, one time that the direct effect of FAMEs in membrane preparation decreased the activity of Na(+)/K(+)-ATPase. The biochemical changes caused by the compounds were significant and may negatively influence the development and survival of C. quinquefasciatus larvae.

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21-Benzylidene Digoxin: A Proapoptotic Cardenolide of Cancer Cells That Up-Regulates Na,K-ATPase and Epithelial Tight Junctions

Cited by 33 publications

References 110 publications

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

Evaluation of neuroprotective activity of digoxin and semisynthetic derivatives against partial chemical ischemia

The Influence of Fatty Acid Methyl Esters (FAMEs) in the Biochemistry and the Na+/K+-ATPase Activity of Culex quinquefasciatus Larvae

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