Selenium nanoparticles act as an intestinal p53 inhibitor mitigating chemotherapy-induced diarrhea in mice.

Selenium, at high-dose levels approaching its toxicity, protects tissues from dose-limiting toxicities of many cancer chemotherapeutics without compromising their therapeutic effects on tumors, there by allowing the delivery of higher chemotherapeutic doses to achieve increased cure rate. In this regard, selenium nanoparticles (SeNPs), which show the lowest toxicity among extensively investigated selenium compounds including methylselenocysteine and selenomethionine, are more promising for application. The key issue remains to be resolved is whether low-toxicity SeNPs possess a selective protective mechanism. p53 or p53-regulated thrombospondin-1 has each been confirmed to be an appropriate target for therapeutic suppression to reduce side effects of anticancer therapy. The present study demonstrated that SeNPs transiently suppressed the expression of many intestinal p53-associated genes in healthy mice. SeNPs did not interfere with tumor-suppressive effect of nedaplatin, a cisplatin analogue; however, effectively reduced nedaplatin-evoked diarrhea. Nedaplatin-induced diarrhea was associated with activation of intestinal p53 and high expression of intestinal thrombospondin-1. The preventive effect of SeNPs on nedaplatin-induced diarrhea was correlated with a powerful concomitant suppression of p53 and thrombospondin-1. Moreover, the high-dose SeNPs used in the present study did not suppress growth nor caused liver and kidney injuries as well as alterations of hematological parameters in healthy mice. Overall, the present study reveals that chemotherapeutic selectivity conferred by SeNPs involves a dual suppression of two well-documented targets, the p53 and thrombospondin-1, providing mechanistic and pharmacologic insights on low-toxicity SeNPs as a potential chemoprotectant for mitigating chemotherapy-induced diarrhea.

Trivalent chromium inhibits TSP-1 expression, proliferation, and O-GlcNAc signaling in vascular smooth muscle cells in response to high glucose in vitro.

Trivalent chromium (Cr(3+)) is a mineral nutrient reported to have beneficial effects in glycemic and cardiovascular health. In vitro and in vivo studies suggest that Cr(3+) supplementation reduces the atherogenic potential and lowers the risk of vascular inflammation in diabetes. However, effects of Cr(3+) in vascular cells under conditions of hyperglycemia, characteristic of diabetes, remain unknown. In the present study we show that a therapeutically relevant concentration of Cr(3+) (100 nM) significantly downregulates a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in human aortic smooth muscle cells (HASMC) stimulated with high glucose in vitro. Promoter-reporter assays reveal that this downregulation of TSP-1 expression by Cr(3+) occurs at the level of transcription. The inhibitory effects of Cr(3+) on TSP-1 were accompanied by significant reductions in O-glycosylation of cytoplasmic and nuclear proteins. Using Western blotting and immunofluorescence studies, we demonstrate that reduced protein O-glycosylation by Cr(3+) is mediated via inhibition of glutamine: fructose 6-phosphate amidotransferase, a rate-limiting enzyme of the hexosamine pathway, and O-linked N-acetylglucosamine (O-GlcNAc) transferase, a distal enzyme in the pathway that controls intracellular protein O-glycosylation. Additionally, we found that Cr(3+) attenuates reactive oxygen species formation in glucose-stimulated HASMC, suggesting an antioxidant effect. Finally, we report an antiproliferative effect of Cr(3+) that is specific for high glucose and conditions triggering elevated protein O-glycosylation. Taken together, these findings provide the first cellular evidence for a novel role of Cr(3+) to modulate aberrant vascular smooth muscle cell function associated with hyperglycemia-induced vascular complications.

Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture.

Resveratrol, a naturally occurring polyphenol, has been reported to be an anti-tumor and chemopreventive agent. Recent data show that it may also exert anti-angiogenic effects. We hypothesized that the anti-angiogenic activity of resveratrol may be caused by modulation of tumor cell release of thrombospondin-1 (TSP1) and vascular endothelial growth factor (VEGF) into the extracellular matrix, leading to vascular endothelial cell (VEC) apoptosis. We therefore evaluated the effects of resveratrol on melanoma cell lines co-cultured with vascular endothelial cells in monolayer and in three dimensional spheroids. We found that resveratrol stimulated isolated VEC proliferation, while it caused growth inhibition of VECs grown with melanoma cells in three-dimensional co-culture. This effect was associated with increased melanoma cell expression of tumor suppressor protein 53 and matrix protein TSP1, as well as decreased hypoxia-driven expression of hypoxia inducible factor-1α and inhibition of VEGF production.