Suppression of Colorectal Oncogenesis by Selenium-Enriched Milk Proteins: Apoptosis and K-ras Mutations

Abstract

The chemical form and bioavailability of dietary selenium may influence its protectiveness against colorectal cancer. Selenium is readily incorporated into milk proteins by feeding cows with selenized-yeast. This study examined whether a dairy source of organic selenium (as milk proteins) is more effective than a yeast source at inhibiting oncogenesis in carcinogentreated mice and whether it regulates the homeostatic response to carcinogen-induced DNA damage. Dietary interventions are as follows: selenium-enriched milk protein isolate (Tatura-Bio Se; 0.5 or 1 ppm selenium) or milk protein control and selenized-yeast (Sel-Plex; 1 or 4 ppm selenium) with casein or casein alone as control. After 4 weeks on diet, mice received a single azoxymethane (10 mg/kg) injection to induce mutations and were killed 6 hours later. Measures were as follows: plasma selenium, cell proliferation, and acute apoptotic response to azoxymethane (AARGC). Separate groups of mice on the same diets were given 4 weekly azoxymethane (15 mg/kg) injections to induce oncogenesis. Mice were killed 6 or 30 weeks after the last azoxymethane injection. Measures were as follows: aberrant crypt foci (ACF), cancers, and K-ras mutations. Dairy-selenium at 1 ppm significantly suppressed ACF and cancers, whereas yeastselenium at an equivalent selenium intake had no effect. Dairy-selenium significantly increased plasma selenium levels and AARGC, and reduced cell proliferation and frequency of Kras mutations in ACF relative to an equivalent dose of selenium from yeast. Selenium-enriched milk protein isolate is superior to selenized-yeast in terms of its bioavailability and capacity to suppress oncogenesis. Suppression may be a consequence of enhanced apoptotic deletion of azoxymethane-induced DNA lesions and the subsequent reduction in frequency of K-ras mutations. [Cancer Res 2008;68(12):4936-44]

Toward Understanding Success and Failures in the Use of Selenium for Cancer Prevention

“…The efficacy of dietary Se supplementation might be further enhanced through the use of Se-enriched plant-or animal-derived foods, probably due to better Se bioavailability and/or different metabolic conversion. Selenized proteins isolated from the milk of cows fed a Se-supplemented diet and selenized broccoli protected the large intestine of rodents against chemically-induced carcinogenesis (23,34). Se-enrichment of broccoli and other cruciferous vegetables might be particularly suitable for cancer prevention, as those plants contain high amounts of glucosinolates that are capable of inducing Nrf2-mediated production of cellular antioxidant enzymes (6).…”

Selenium-enriched fermented milk: A suitable dairy product to improve selenium intake in humans

“…Recently, there has been evidence that the benefits of Se depend on the form in which it is ingested (Hu, McIntosh, Le Leu, Woodman, & Young, 2008;Rayman, Goenaga Infante, & Sargent, 2008). Other authors have established that organic selenium is preferable to inorganic (Bordony, Daresi & Malaguti, 2008;Rayman, 2004;Schrauzer, 2000).…”

Selenized milk casein in the diet of BALB/c nude mice reduces growth of intramammary MCF-7 tumors

“…Our results add a new dimension to the findings that dietary Se prevents oncogenesis in chemical-induction models of mammary and colorectal cancer [6,12], and to the growing body of evidence that Se compounds are effective against established tumors [17]. Selenium is thought to affect tumor growth by inducing cell cycle arrest and apoptosis [18-20].…”

“…The supplementation of Se-yeast in a cow’s diet is the most effective method for increasing milk Se content, where Se is incorporated into milk proteins as selenomethionine during milk synthesis [11]. Consumption of 1 ppm Se from selenized milk protein increased apoptosis and decreased proliferation of chemically induced colon tumors, and decreased the number of mice with tumors 30 weeks after carcinogen exposure [12]. Effects of dairy Se on mammary tumor development has not previously been investigated although organic forms of Se providing 2 ppm dietary Se decreased by 50% the number of chemically induced mammary tumors 22 weeks after carcinogen exposure in rats [6].…”