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

Departments of ¹ Medicine and ² General Practice, Flinders Cancer Control Alliance, Flinders University of South Australia, Adelaide, Australia

Requests for reprints: Ying Hu, Department of Medicine/Gastroenterology, Flinders Medical Centre, Flinders University of South Australia, Bedford Park, Adelaide, 5042, Australia. Phone: 61-8-8204-5170; Fax: 61-8-8204-3943; E-mail: ying.hu{at}flinders.edu.au.

Key Words: selenium • apoptosis • K-ras mutation • aberrant crypt foci • colon cancer

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 carcinogen-treated 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 yeast-selenium at an equivalent selenium intake had no effect. Dairy-selenium significantly increased plasma selenium levels and AARGC, and reduced cell proliferation and frequency of K-ras 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]