Effects of 5,6-benzoflavone, indole-3-carbinol (I3C) and diindolylmethane (DIM) on chemically-induced mammary carcinogenesis: Is DIM a substitute for I3C?

Abstract

Abstract. the abilities of 5,6-benzoflavone (5,6-BF, a synthetic flavonoid), indole-3-carbinol (I3C, a plant derived product) or diindolylmethane (DIM, a condensation product of I3C) to alter the induction of mammary cancers induced by the carcinogens 7,12-dimethylbenzanthracene (DMBA) or N-methyl-N-nitrosourea (MNU) were evaluated. Interestingly, the first two agents act as aryl hydrocarbon receptor (AhR) agonists, while DIM does not. The agents were initially examined for their ability to inhibit DMBA-induced mammary carcinogenesis. Agents were administered for 14 days starting 7 days prior to a single dose of the carcinogen. Evaluated over an extensive range of doses (165, 550 and 1650 ppm in the diet), 5,6-BF caused a dose-dependent decrease of mammary cancers. In addition, 5,6-BF at doses of 1650 and 165 ppm in the diet blocked the induction of DMBA-induced DNA adducts in the mammary gland by approximately 85% and 45%, respectively. In contrast, DIM (180 or 20 mg/kg BW/day) failed to block induction of DMBA tumors. The effect of these agents on the promotion/progression phase of carcinogenesis using the MNU mammary cancer model was also determined. 5,6-BF (1650 or 165 ppm in the diet), I3C (180 or 60 mg/kg BW/day administered by gavage), or DIM (180 or 60 mg/kg BW/day by gavage) were initiated 5 days after the administration of MNU, and continually thereafter. 5,6-BF decreased MNUinduced mammary tumor multiplicity by 40-60%. I3C reduced tumor multiplicity at the high dose, while DIM at either dose had minimal effects on tumor multiplicity. Thus, 5,6-BF and I3C were highly effective against initiation of DMBA-induced mammary carcinogenesis, and were also effective against MNU-induced tumors during the promotion/progression phase of carcinogenesis. In contrast, DIM had minimal effects in either model; arguing that administration of DIM is not analogous to administration of I3C.

Plants vs. Cancer: A Review on Natural Phytochemicals in Preventing and Treating Cancers and Their Druggability

“…DIM, along with I3C were found to induce Nrf2-mediated phase II drug metabolizing (GSTm2, UGT1A1, and NQO1) and antioxidant (HO-1 and SOD1) genes and also shown synergism with isothiocyanates, such phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) [82]. Lubet et al found that I3C acts as AhR agonist in mammary cancers while DIM does not, and DIM is not analogous to I3C in exerting their anticarcinogenesis effects [83]. DIM and I3C may act more effectively at earlier stage of prostate carcinogenesis and likely through a combination of effects on steroid hormones and/or xenobiotic metabolism pathway [84].…”

Effects on Gene Expression in Rat Liver after Administration of RXR Agonists: UAB30, 4-Methyl-UAB30, and Targretin (Bexarotene)

“…We showed that these genes were highly induced by the Ah receptor agonist 5,6-benzoflavone ). UAB30 clearly activated Ah receptor related genes (Table 4), and our prior findings showed that compounds that activate this receptor inhibit DMBA-induced mammary cancer and aflatoxin-induced liver cancer (Grubbs et al, 1995;Lubet et al, 2011). Therefore, we tested UAB30 (200 ppm) in the DMBAinduced mammary model, which reduced cancers by .80%, as much as a suboptimal dose (400 ppm) of 5,6 benzoflavone ( Fig.…”

“…This model examines the ability of an agent to block the initiation of mammary carcinogenesis (positive) in rats. We have published multiple articles using this model and recently showed that 5, 6 benzoflavone was highly effective (Grubbs et al, 1995;Lubet et al, 2011). In brief, female Sprague-Dawley rats were administered UAB30 (200 ppm), 5, 6 benzoflavone (400 ppm), or control diet from 43 days of age until 57 days of age.…”

Cadmium Accumulation by Plants of Brassicaceae Family and Its Connection with Their Primary and Secondary Metabolism

“…3.3), and glutathione, the most important protective non-protein thiol compound (Mugford et al 2011). Glucosinolates, mustard oil glycosides, represent one of the bioactive sulphur-containing secondary metabolites in plants, which occur almost only in members of order Brassicales Hamsa et al 2011;Lubet et al 2011;Malaguti et al 2011;Rajendran et al 2011;Razis et al 2011;Sharma et al 2011;Shimamoto et al 2011;Starrett and Blake 2011;Wiczk and Herman-Antosiewicz 2011). Their structure is based on ά-D-glucopyranose residue, which is linked via a sulphur atom to a (Z)-Nhydroximinosulphate ester.…”