Differences of lipid membrane modulation and oxidative stress by digoxin and 21-benzylidene digoxin

Silva, Lilian N. D.; Pessôa, Marco Túlio C.; Alves, Silmara L.G.; Venugopal, Jessica; Cortes, Vanessa Faria; Santos, Herica L.; Villar, José Augusto Ferreira Perez; Barbosa, Leandro A.

doi:10.1016/j.yexcr.2017.07.017

Cited by 18 publications

(17 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are reports in the literature in which treatment with CTS has led to a build-up in ROS production of in different cell lines, which might lead to cell damage and perform as second messengers in cellular signaling events, leading to apoptosis. 44,49 Based on these studies, we treated N2a cells with the steroids alone ( Figure 8B) and in none of the groups did the lipid peroxidation levels change. Our finding, then, confirms that CTS treatment does not modulate the membrane damage observed during the ischemic induction.…”

Section: Discussionmentioning

confidence: 99%

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

Gonçalves

Valadares

Alves

et al. 2019

J of Cellular Biochemistry

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…36 However, the potential of chronic inflammation as a therapeutic target to halt the HCC progression is still obscure. Moreover, while glucocorticoids (GCs) have been shown to enhance cell proliferation and inhibit apoptosis for most mammalian cell types, 43,44 there have not been sufficient in vitro tests of GCs on cancer cells to indicate the potential benefit of GCs on carcinogenesis. Furthermore, while the use of GCs may be harmful for skin cancer, lymphoma and breast cancer, 45,46 effects of GCs on the progression of HCC have not been fully investigated by in vivo studies.…”

Section: Discussionmentioning

confidence: 99%

<p>Hydrocortisone Suppresses Early Paraneoplastic Inflammation And Angiogenesis To Attenuate Early Hepatocellular Carcinoma Progression In Rats</p>

Liu¹,

Cui²,

Niu³

et al. 2019

OTT

View full text Add to dashboard Cite

Background: Inflammation is implicated in both hepatic cirrhosis development and hepatocellular carcinogenesis, and treatment with long-acting glucocorticoid dexamethasone prevented liver carcinogenesis in mice. However, it is unclear whether glucocorticoids have anti-inflammatory effect on hepatocellular carcinoma (HCC) and if short-acting glucocorticoids (with fewer adverse effects) inhibit paraneoplastic inflammation and HCC progression. Methods: To investigate whether different types of anti-inflammatory agents attenuate HCC progression, the current study compared effects of treatments with hydrocortisone (a shortacting glucocorticoid) or aspirin on HCC progression. HCC was induced in diethylnitrosaminetreated rats which were randomly divided into 4 groups (n=8), respectively receiving orally once daily vehicle, glucuronolactone, glucuronolactone+hydrocortisone, and glucuronolactone +aspirin. Diethylnitrosamine (DEN) was given to rats in drinking water (100mg/L) to induce HCC. At weeks 12 and 16 post-induction, effects were compared on HCC nodule formation, microvessel density, and macrophage infiltration, and levels of paraneoplastic protein expression of tumor necrosis factor (TNF)-α, p38 mitogen-activated protein kinase (p38), phosphorylated p38 (p-p38), nuclear factor (NF)-κB, interleukin (IL)-10, hepatocyte growth factor (HGF), transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF). Results: Compared to the model and glucuronolactone alone groups, HCC nodule number and microvessel density in the glucuronolactone+hydrocortisone group were significantly lower at week 12. At week 12 but not week 16, significantly lower levels of macrophages, TNF-α, p-p38, NF-κB, IL-10, HGF, TGF-β1 and VEGF were observed in the paraneoplastic tissue of the glucuronolactone+hydrocortisone group when compared with the control and glucuronolactone groups. Conclusion: The results suggest that hydrocortisone treatment reduces macrophage polarization, expression of inflammatory and anti-inflammatory cytokines, and angiogenesis in paraneoplastic tissue, and attenuates early HCC progression. Although hydrocortisone did not have attenuation effect on advanced solid tumor, the current study shows the potential benefits and supports potential clinical use of hydrocortisone in attenuating early progression of HCC, which is through suppressing paraneoplastic inflammation and angiogenesis.

show abstract

Differences of lipid membrane modulation and oxidative stress by digoxin and 21-benzylidene digoxin

Cited by 18 publications

References 40 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

<p>Hydrocortisone Suppresses Early Paraneoplastic Inflammation And Angiogenesis To Attenuate Early Hepatocellular Carcinoma Progression In Rats</p>

Contact Info

Product

Resources

About