Pharmacological mechanisms of the anticancer action of sodium selenite against peritoneal cancer in mice.

Peritoneal carcinomatosis has an extremely poor overall prognosis and remains one of the greatest oncologic challenges. Prior studies in mice show that sodium selenite administered intraperitoneally is highly effective in inhibiting cancer cells implanted in the peritoneal cavity. However, the pharmacological mechanism remains unclear. The present study revisited the therapeutic effect of selenite and elucidated its mechanism of action. We found that intraperitoneal delivery of selenite to cancer cells in the peritoneal cavity of mice rapidly and robustly killed the cancer cells, with a therapeutic efficacy higher than that of cisplatin. The action of selenite was associated with the following pharmacological mechanisms. 1) Favorable drug distribution: selenite increased selenium levels in the cancer cells by 250-fold, while in normal tissues only by 7-fold. 2) Optimal selenium form: selenite was converted in the cancer cells mainly into selenium nanoparticles (SeNPs), which are more efficient than selenite in producing reactive oxygen species (ROS). 3) Persistent hijacking of two pro-survival systems to generate ROS: selenite did not impair thioredoxin- and glutaredoxin-coupled glutathione systems, which facilitate SeNPs to generate ROS and caused severe organelle injury and apoptotic response in the cancer cells. Overall, these mechanisms tend to maximize the potential of selenite in producing ROS in cancer cells and underlie selenite as a candidate therapeutic agent for peritoneal carcinomatosis.