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Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation

Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cys...

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Autores principales: Santos, Inês, Ramos, Cristiano, Mendes, Cindy, Sequeira, Catarina O., Tomé, Catarina S., Fernandes, Dalila G.H., Mota, Pedro, Pires, Rita F., Urso, Donato, Hipólito, Ana, Antunes, Alexandra M.M., Vicente, João B., Pereira, Sofia A., Bonifácio, Vasco D. B., Nunes, Sofia C., Serpa, Jacinta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836284/
https://www.ncbi.nlm.nih.gov/pubmed/31635026
http://dx.doi.org/10.3390/nu11102523
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author Santos, Inês
Ramos, Cristiano
Mendes, Cindy
Sequeira, Catarina O.
Tomé, Catarina S.
Fernandes, Dalila G.H.
Mota, Pedro
Pires, Rita F.
Urso, Donato
Hipólito, Ana
Antunes, Alexandra M.M.
Vicente, João B.
Pereira, Sofia A.
Bonifácio, Vasco D. B.
Nunes, Sofia C.
Serpa, Jacinta
author_facet Santos, Inês
Ramos, Cristiano
Mendes, Cindy
Sequeira, Catarina O.
Tomé, Catarina S.
Fernandes, Dalila G.H.
Mota, Pedro
Pires, Rita F.
Urso, Donato
Hipólito, Ana
Antunes, Alexandra M.M.
Vicente, João B.
Pereira, Sofia A.
Bonifácio, Vasco D. B.
Nunes, Sofia C.
Serpa, Jacinta
author_sort Santos, Inês
collection PubMed
description Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H(2)S-synthesizing enzyme cystathionine β-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H(2)S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PURE(G4)-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PURE(G4)-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.
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spelling pubmed-68362842019-11-21 Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation Santos, Inês Ramos, Cristiano Mendes, Cindy Sequeira, Catarina O. Tomé, Catarina S. Fernandes, Dalila G.H. Mota, Pedro Pires, Rita F. Urso, Donato Hipólito, Ana Antunes, Alexandra M.M. Vicente, João B. Pereira, Sofia A. Bonifácio, Vasco D. B. Nunes, Sofia C. Serpa, Jacinta Nutrients Article Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine/glutamate antiporter system Xc (xCT) and the H(2)S-synthesizing enzyme cystathionine β-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H(2)S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PURE(G4)-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PURE(G4)-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity. MDPI 2019-10-19 /pmc/articles/PMC6836284/ /pubmed/31635026 http://dx.doi.org/10.3390/nu11102523 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Santos, Inês
Ramos, Cristiano
Mendes, Cindy
Sequeira, Catarina O.
Tomé, Catarina S.
Fernandes, Dalila G.H.
Mota, Pedro
Pires, Rita F.
Urso, Donato
Hipólito, Ana
Antunes, Alexandra M.M.
Vicente, João B.
Pereira, Sofia A.
Bonifácio, Vasco D. B.
Nunes, Sofia C.
Serpa, Jacinta
Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation
title Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation
title_full Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation
title_fullStr Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation
title_full_unstemmed Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation
title_short Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation
title_sort targeting glutathione and cystathionine β-synthase in ovarian cancer treatment by selenium–chrysin polyurea dendrimer nanoformulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836284/
https://www.ncbi.nlm.nih.gov/pubmed/31635026
http://dx.doi.org/10.3390/nu11102523
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