Back to Search
Start Over
Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium-Chrysin Polyurea Dendrimer Nanoformulation
- Source :
- Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Nutrients, Volume 11, Issue 10, Nutrients, Vol 11, Iss 10, p 2523 (2019)
- Publication Year :
- 2019
-
Abstract
- 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 H2S-synthesizing enzyme cystathionine &beta<br />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 H2S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PUREG4-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@PUREG4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.
- Subjects :
- 0301 basic medicine
Dendrimers
hydrogen sulfide (H2S)
Cell Survival
Polymers
Cystine
selenium chrysin (SeChry)
Cystathionine beta-Synthase
lcsh:TX341-641
Antineoplastic Agents
medicine.disease_cause
Article
03 medical and health sciences
chemistry.chemical_compound
Selenium
0302 clinical medicine
SDG 3 - Good Health and Well-being
Cell Line, Tumor
medicine
Humans
Chrysin
cysteine
Cysteine metabolism
Flavonoids
Ovarian Neoplasms
Nutrition and Dietetics
biology
cystine/glutamate antiporter system Xc- (xCT)
cystathionine β-synthase (CBS)
Glutathione
Cystathionine beta synthase
glutathione (GSH)
Nanostructures
HaCaT
030104 developmental biology
ovarian cancer
chemistry
platinum drugs
030220 oncology & carcinogenesis
folate-targeted polyurea dendrimers
Cancer research
biology.protein
Female
lcsh:Nutrition. Foods and food supply
Oxidative stress
Cysteine
Food Science
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Nutrients, Volume 11, Issue 10, Nutrients, Vol 11, Iss 10, p 2523 (2019)
- Accession number :
- edsair.doi.dedup.....f4d080ac5ca3b8ec37597e5bf46cbb8a