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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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. |
format | Online Article Text |
id | pubmed-6836284 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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