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

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 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 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.

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

“…As a carbon source, glutamine supplies the tricarboxylic acid (TCA) cycle with oxaloacetate, α-ketoglutarate, and acetyl-CoA, thus being responsible for ATP and macromolecules synthesis, preferentially replacing glucose in certain tumors [ 15 , 16 , 17 ]. Furthermore, glutamine is a precursor of glutamate, which is necessary for the synthesis of non-essential amino acids and glutathione (GSH), the most important reactive oxygen species (ROS) scavenger and detoxifying agent [ 18 , 19 ].…”

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine Sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance

“…We have previously shown the efficacy of PUREG4-FA2 nanoparticles as a vehicle to deliver a cytotoxic selenium-chrysin compound to ovarian cancer cells [28]. In this study, we have shown the efficacy of those nanoparticles as a vehicle to delivery also L-BSO to ovarian cancer cells.…”

“…Our previous studies suggested a stronger dependence of ES2 cells on GSH turnover compared with OVCAR3 cells [12,13], which was also evidenced in this study, as higher EC 50 of free l-BSO and l-BSO@PURE G4 -FA 2 were determined for ES2 compared with OVCAR3 cells. Furthermore, concerning resistance to carboplatin, we have reported that upon carboplatin exposure ES2 produce higher levels of GSH [11] together with an accelerated GSH turnover, compared with OVCAR3 [28]. Therefore, our greatest achievements in this study were the effective use of l-BSO@PURE G4 -FA 2 nanoparticles to the specific targeting of malignant cells, decreasing the harmful effects of l-BSO in non-malignant cells, and the similar effective targeting of ovarian cancer cells with different levels of chemoresistance.…”

“…The use of folate-targeted dendrimers is an emergent approach in cancer-targeted chemotherapy [27]. As we recently reported [28], folate-targeted polyurea dendrimer generation four (PURE G4 -FA 2 ) nanoparticles are a suitable drug delivery system. Of notice, ovarian cancer cells express higher levels of folate receptor α (FA-Rα) than normal cells [29] and FA-Rα targeted therapy is an assay commonly tested in in vitro and in vivo models of ovarian cancer [30].…”

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

“…Among different adaptive strategies adopted by chemoresistant cancer cells, chemoresistance has been associated with alterations in glutathione (GSH) and cysteine dynamics. We and others showed that, overall, cysteine flux in cancer cells and the expression and activity of enzymes involved in cysteine metabolism interfere with the response to chemotherapy by ultimately abrogating the effect of oxidative or alkylating drugs [ 3 , 4 , 5 , 6 , 7 ]. On the other hand, enzymes function is influenced by the oxidative stress.…”