Cancer chemoprevention with the adrenocortical steroid dehydroepiandrosterone and structural analogs.

Dehydroepiandrosterone (DHEA) is an adrenocortical steroid that produces broad-spectrum cancer chemopreventive action in mice and rats. In the mouse two-stage skin tumorigenesis model, DHEA treatment inhibits tumor initiation, as well as tumor promoter-induced epidermal hyperplasia and promotion of papillomas. There is considerable evidence that DHEA exerts its anti-proliferative and tumor-preventive action through the inhibition of glucose-6-phosphate dehydrogenase and the pentose phosphate pathway, which generate NADPH (required for mixed-function oxidase activation of chemical carcinogens, as well as for deoxyribonucleotide synthesis) and ribose 5-phosphate (also required for deoxyribonucleotide synthesis). Long-term DHEA treatment of mice also reduces weight gain (apparently by enhancing thermogenesis), and appears to produce many of the beneficial effects of food restriction, which have been shown to inhibit the development of many age-associated diseases, including cancer. Using the mouse two-stage skin tumorigenesis model, we found that adrenalectomy completely reverses the anti-hyperplastic and antitumor-promoting effects of food restriction. It is not unlikely that food restriction stimulates enhanced levels of adrenocortical steroids, such as the anti-inflammatory glucocorticoids and DHEA, which in turn mediate the tumor-inhibitory effect of underfeeding.