The selenium metabolite selenodiglutathione induces p⁵³ and apoptosis: relevance to the chemopreventive effects of selenium?

Abstract

Selenodiglutathione (SDG), the initial metabolite of selenite, is shown to be a more powerful inhibitor of cell growth in vitro than selenite itself. This has been established both with mouse erythroleukaemia (MEL) cells and an ovarian cell line (A2780) which is known to contain wild-type p53. Other seleno-compounds, such as selenomethyl selenocysteine (SMS) and dimethyl selenoxide (DMS), which are potent chemopreventive agents and are known to be metabolized to methylated selenium derivatives directly rather than via SDG, are also growth inhibitory to both MEL and A2780 cells, although less so than SDG or selenite. However, cells growth-inhibited by DMS are more viable than cells growth-inhibited to the same extent by SDG or selenite, suggesting that the methylated seleno-compounds may inhibit cell growth in a different manner from that of SDG or selenite. Our studies of the mechanism of growth inhibition by SDG, have established two facts. First, SDG induces p53 protein levels in cells that contain wild-type p53 (A2780 cells), suggesting that SDG induces the DNA damage-recognition pathway. Secondly, SDG induces apoptosis in MEL cells, as judged by flow cytometry and formation of nucleosomal DNA ladders. However, since p53 mutations have been found to be targetted events in all MEL cells examined, our evidence suggests that induction of apoptosis by SDG is not absolutely dependent on the p53 response pathway.

Expression of p53 Enhances Selenite-Induced Superoxide Production and Apoptosis in Human Prostate Cancer Cells

“…We also showed that overexpression of MnSOD prevented cell death from selenite treatment (26). In addition, studies from other laboratories have shown that selenium compounds modulated p53 (14,(27)(28)(29). Taken together, these results suggest that superoxide and p53 may be involved in apoptosis induced by selenite.…”

“…Recent studies have shown that selenite treatment up-regulated p53 and induced p53 phosphorylation on Ser15 to induce caspasemediated apoptosis (27)(28)(29). However, the link between superoxide production and p53 regulation in selenite-induced apoptosis has not been elucidated.…”

Selenium, Apoptosis, and Colorectal Adenomas

“…Our results concerning the relation between selenium and apoptosis in humans were contrary to results from several laboratory studies, suggesting that selenium increased anticancer apoptotic activity (34)(35)(36)(37)(38)(39)(40)(41)(42). There are several reasons that our results may differ from laboratory studies.…”

“…The possibility that selenium may increase anticancer apoptotic activity has been suggested by several carcinogenesis studies (34)(35)(36)(37)(38)(39)(40)(41)(42). It is unclear how selenium might induce apoptosis; however, several selenium metabolites, such as hydrogen selenide, methylselenol, and selenodiglutathione, are being researched (43)(44)(45).…”

Selenium and Vitamin E for Prostate Cancer: Post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) Status

“…Furthermore, whether an intact p53 system is necessary for any anticarcinogenic effects of selenium or vitamin E remains a contentious issue. While Lanfear et al (91) reported that selenium metabolite selenodiglutathione caused apoptosis in cells with wild-type and mutated p53 status (murine erythroleukemia and human ovarian carcinoma), Jiang et al (92) reported that selenite-induced apoptosis of LNCaP cells depends on intact p53 activity. The specific role of p53 in seleniuminduced PCa cell apoptosis, and perhaps in turn whether selenium acts preferentially via the intrinsic or extrinsic pathways, remains an active area of research.…”