Anticancer mechanism of equol in 7,12-dimethylbenz(a)anthracene-treated animals

Abstract

This study investigated the anticancer effects of equol, the major metabolite of the antioxidant phytochemical daidzein, on 7,12-dimethylbenz(a)anthracene (DMBA)-treated animals and explored its anticancer mechanism. The experiment consisted of two parts. In the first part, Sprague-Dawley rats were given equol daily at 5 and 25mg/kg body weight (BW) for 8 weeks after a single dose of DMBA (100mg/kg BW). As a control, rats were divided into vehicle alone and DMBA alone groups. Equol administration at a higher dose effectively suppressed tumor formation and PCNA over-expression. The activation of p53 by equol subsequently affected the cyclin-dependent kinase inhibitor p21Cip1. This was associated with equol-induced apoptosis in mammary gland tumors, as evidenced by the decreased Bcl-2 expression and increased Bax expression, together with the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). In the second part, oral pre-administration of equol to mice which received DMBA intragastrically twice a week for 2 weeks significantly decreased their levels of biomarkers (thiobarbituric acid-reactive substances, carbonyl content and serum 8-hydroxy-2-deoxyguanosine) of DMBA-induced oxidative stress. Although several antioxidant enzymes were down-regulated in mice treated with DMBA alone, pre-administration of equol blocked much of this effect, increasing catalase and superoxide dismutase activity in a dose-dependent manner. Although equol did not affect the ratio of oxidized to reduced glutathione, it activated the glutathione peroxidase and glutathione reductase enzymes, and this effect was significant at a dose of 25 mg equol/kg body weight. DMBA treatment induced apoptosis, as shown by a decrease in the Bcl-2 levels and an increase in the levels of Bax, cleaved caspase-3 and poly(ADP-ribose) polymerase. These apoptotic effects were also reversed by equol at all doses tested. Based on these results, equol possesses anticancer activity that suppresses tumor formation via apoptosis induction in rats with DMBA-induced mammary gland tumors. In addition, equol showed a hepatic protective effect by acting as an antioxidant and by reducing apoptosis.