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.

Selenium nanoparticles are more efficient than sodium selenite in producing reactive oxygen species and hyper-accumulation of selenium nanoparticles in cancer cells generates potent therapeutic effects.

We have previously demonstrated that selenium nanoparticles (SeNPs) administered via oral route possess similar capacities of increasing selenoenzyme activities as the extensively examined sodium selenite, selenomethionine and methylselenocysteine, and yet display the lowest toxicity among these selenium compounds in mouse models. However, the low toxicity of SeNPs found in mammalian systems would lead to the interpretation that the punctate distribution of elemental selenium found in cultured cancer cells subjected to selenite treatment that triggers marked cytotoxicity represents a detoxifying mechanism. The present study found that SeNPs could be reduced by the thioredoxin- or glutaredoxin-coupled glutathione system to generate ROS. Importantly, ROS production by SeNPs in these systems was more efficient than by selenite, which has been recognized as the most redox-active selenium compound for ROS production. This is because multiple steps of reduction from selenite to selenide anion are required; whereas only a single step reduction from the elemental selenium atom to selenide anion is needed to trigger redox cycling with oxygen to produce ROS. We thus speculated that accumulation of SeNPs in cancer cells would result in a strong therapeutic effect, rather than serves a detoxification function. Indeed, we showed herein that preformed SeNPs generated a potent therapeutic effect in a mouse model due to rapid, massive and selective accumulation of SeNPs in cancer cells. Overall, for the first time, we demonstrate that SeNPs have a stronger pro-oxidant property than selenite and hyper-accumulation of SeNPs in cancer cells can generate potent therapeutic effects.