Targeting Glutathione and Cystathionine ß-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 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 ß-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.

Impairment in consolidation of learned place preference following dopaminergic neurotoxicity in mice is ameliorated by N-acetylcysteine but not D1 and D2 dopamine receptor agonists.

Some of the major concerns related to methamphetamine (METH) abuse are the neuronal damage inflicted at dopamine (DA) nerve terminals and the cognitive deficits observed in human METH abusers. We have shown that a high dose of METH selectively depleted dopaminergic markers in striatum, frontal cortex and amygdala of Swiss Webster mice, and impaired learned place preference. In this study, we investigated whether deficits in consolidation of place learning, as a consequence of METH neurotoxicity, underlie the underperformance of cocaine conditioned place preference (CPP). Administration of METH (5 mg/kg x 3) to Swiss Webster mice decreased striatal tyrosine hydroxylase (TH) immunoreactive neurons and significantly increased glial fibrillary acidic protein (GFAP) expression, confirming the neurotoxic potential of METH in mice. This treatment significantly attenuated the establishment of cocaine (15 mg/kg) CPP compared to control. To investigate whether manipulation of the consolidation phase improves learned place preference, mice were trained by cocaine and received daily post-training injections of DA receptor agonists or N-acetylcysteine (NAC). As memory consolidation occurs shortly after training, drugs were administered either immediately or 2 h post-training. Immediate post-training administration of the D1 DA receptor agonist SKF38393 (5, 10, and 20 mg/kg) or the D2 DA receptor agonist quinpirole (0.25, 0.5, and 1.0 mg/kg) did not improve the establishment of CPP following METH neurotoxicity. However, immediate but not delayed NAC administration (50 and 100 mg/kg) enhanced cocaine CPP following METH neurotoxicity and had no effect on control CPP. The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of CPP training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls. Results suggest that METH-induced dopaminergic neurotoxicity is associated with impairment of consolidation of learned place preference, and that this impairment is improved by immediate post-training administration of the glutathione precursor NAC and not by D1 or D2 DA receptor agonists. Restoration of brain glutathione levels immediately post-training may facilitate the consolidation process.