Studies as early as 1969 suggested that there was an inverse correlation between dietary selenium levels and cancer mortality rates.45 Accompanying the discovery of the enzyme GPx, the chemopreventative action of selenium was initially attributed to its presence in anti-oxidant enzymes such as GPx and other selenoproteins. In 1996 Clark found that selenium supplementation, 200 mg/ day in the form of selenium-enriched yeast, reduced the risk of prostate, colon and lung cancer by up to 48% in subjects with a history of skin cancer. The dose of selenium used was higher than the current American 'recommended dietary allowance', and higher than the 90 mg/day required for maintenance of maximum-plasma and whole-blood GPx activities, as established by Duffield.27,46 48 The anti-oxidant explanation for the chemopreventative action of selenium lost popularity as it appeared that supranutritional doses of selenium were necessary for anti-cancer activity.47 Additional evidence that the mechanism of selenium anti-cancer activity was discrete from its nutritional role was provided by studies that showed selenium compounds that were only poorly able to be used for the biosynthesis of selenoproteins also had comparable anticancer activities.49 51
Much work has been directed at elucidating the mechanism of selenium anticancer activity. Studies have used different forms of selenium, commonly sodium selenite and SeMet, which are used in dietary supplements. Observed differences in the type of activity for each form and studies showing contradictory results have hindered finding a simple answer. Generally it is considered that, at nutritional levels, selenium in selenoproteins acts as an anti-oxidant, enhancing cell growth and immune activity. At supranutritional levels, selenium metabolites behave as pro-oxidants and inhibit cell growth, and at even higher concentrations they become toxic.47,48 Numerous mechanisms have been proposed to account for the chemopreventative properties of selenium. These include induction of apoptosis and cell-cycle arrest by low-weight selenium metabolites, such as methylselenol;47,52 55 activation of Ref. 1 by selenomethionine - which leads to increased DNA repair;56 inhibition of enzymes such as
TrxR;48,57,58 and newly discovered selenoproteins with unknown functions, all of which may be shown to play a part in cancer prevention.48
A large number of studies have shown that the generation of low molecular weight selenium metabolites from selenium-containing compounds is critical for their anti-cancer activity.48 51,59,60 Excess natural inorganic and organic selenium is metabolized for excretion in animals by methylation of H2Se; Figure 17.1.12,49 Methylselenol is considered to be the species responsible for the chemopreventative activity of supranutritional doses of dietary supple-ments.48 52,59 Dimethylselenide was excluded as a candidate for anti-cancer activity as dimethylselenoxide, a dimethylselenide precursor, had negligible anti-cancer activity. The fully methylated metabolite, trimethylselenonium ion, was found to have no anti-cancer activity, possibly as it is too rapidly excreted.47,49,59 Methylselenol is too reactive to be administered directly. However, alternative precursors that generate methylselenol endogenously have provided evidence of the importance of methylselenol to anti-cancer activity.
Methylselenocysteine (SeMC) is converted to methylselenol by ^-lyase and is a more direct source of methylselenol than sodium selenite or SeMet (Figure 17.1).52,59 SeMC is a more potent chemopreventative agent than SeMet or sodium selenite, presumably due the more efficient production of methylsele-nol.50,51,59 Additionally, SeMC is more available than SeMet for conversion to methylselenol as it cannot be stored in general proteins (replacing methio-nine).59 L-Se-methylselenocysteine (L-SeMC) has shown much promise as a chemopreventative agent, with lower toxicity than sodium selenite or SeMet, and has been patented for use as a nutriceutical by Pharmase Inc., USA.61
Another source of methylselenol is methylseleninic acid (MSeA, Figure 17.1). This has the advantage of metabolism to methylselenol through reaction with reduced glutathione (GSH); thus it is an effective methylselenol source in cell types that have low concentrations of ^-lyase.52,60A recent study found that methylselenol generated from both MSeA and SeMet (after exposure to methioninase, METase) displayed almost identical actions, that being induction of cell-cycle arrest at G1 and apoptosis (programmed cell death), in Du145 human prostate cancer cells.54 Apoptosis is considered to be the primary cause of cell death by anti-cancer drugs.62 Lu found that SeMet in the absence of METase had no effect on human prostate cancer cells at concentrations as high as 100 mM. In contrast, methylselenol generated from METase-treated SeMet significantly increased apoptosis at concentrations as low as 1 mM SeMet.54
Ip found that MSeA treatment of human premalignant breast cells caused cell-cycle arrest at the Go/G1 stage and increased the rate of apoptosis by five times. Ip suggests that methylselenol may induce apoptosis by upregulating the expression of a number of proteins known to mediate programmed cell death. Selenols exist in vivo as the selenoate anion; these have the potential to form selenylsulfide linkages (—S—SeCH3) that could affect the activity of cysteine-rich proteins.52,63 It has also been proposed that the generation of superoxide from selenoate anions may cause oxidative stress and apoptosis.55,64,65 Spallholz used chemi-luminescence to detect superoxide formation from various selenium-containing compounds.55 They found that putative selenol precursors, such as MSeA and diselenides, generated superoxide whereas monoselenides did not. Interestingly, SeMet alone did not generate superoxide; however, superoxide was detected when SeMet was tested in the presence of METase.55 This gives further credence to the importance of methylselenol in cancer prevention.
A new hypothesis regarding the chemopreventative action of dietary selenium that has stimulated much interest has emerged from the work of Smith and co-workers.56,66 Smith has found that treatment of human lung cells with SeMet appeared to increase repair of DNA damaged by UV radiation and chemical carcinogens such as carboplatin.56 The results suggest that SeMet activates a protein, redox factor Ref. 1, which in turn activates the tumor-suppressor protein p53. In cells lacking the p53 gene there was no observed induction of DNA repair by SeMet. Interestingly, in contrast with many studies, no apoptosis or cell-cycle arrest was observed with SeMet treatment. The tumor-suppressor protein p53 has roles in both induction of apoptosis and enhancement of DNA repair depending on cell type, and often functions poorly in human cancer cells.62,67 Further research to elucidate the activity of selenium compounds in improving DNA repair will certainly be of interest, particularly with the aim of treating people for whom inadequate DNA repair places them at risks for certain cancers.
Inhibition of thioredoxin reductase (TrxR)
The activity of selenoprotein TrxR impacts upon a large range of biological processes.20 Relevant to cancer prevention is the role of TrxR in apoptosis and protection against oxidative stress. Increased activity of TrxR leads to increased levels of reduced thioredoxin (Trx). Reduced Trx is able to bind to apoptosis signalling kinase (ASK-1), resulting in inhibition of apoptosis. On the other hand, inhibition of TrxR can lead to increased ASK-1 activity and subsequent apoptosis.20,68 There are a number of clinically used chemotherapeutic compounds that inhibit TrxR, and evidence that selenium was also an inhibitor of TrxR led to speculation that this may hold the key to its anti-cancer activity.20,48 The findings of a number of studies48,57,68,69 have presented conflicting evidence regarding this hypothesis and it is clear that more research is required to ascertain exactly how selenium acts as a cancer preventative.
Was this article helpful?
Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.