Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3 '-diindolylmethane, a major in vivo product of dietary indole-3-carbinol

Under acidic conditions, indole-3-carbinol (I3C) is converted to a series o f oligomeric products thought to be responsible for the biological effects of dietary I3C. Chromatographic separation of the crude acid mixture of I3C , guided by cell proliferation assay in human MCF-7 cells, resulted in the isolation of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr-1) as a major antiproliferative component. LTr-1 inhibited the growth of both estrogen-de pendent (MCF-7) and -independent (MDA-MB-231) breast cancer cells by approx imately 60% at a non-lethal concentration of 25 mu M. LTr-1 had no apparent effect on the proliferation of MCF-7 cells in the absence of estrogen. LTr -1 was a weak ligand for the estrogen receptor (ER) (IC50 70 mu M) and effi ciently inhibited the estradiol (E-2)-induced binding of the ER to its cogn ate DNA responsive element. The antagonist effects of LTr-1 also were exhib ited in assays of endogenous pS2 gene expression and in cells transiently t ransfected with an estrogen-responsive reporter construct (pERE-vit-CAT). L Tr-1 activated both binding of the aryl hydrocarbon (Ah) receptor to its co gnate DNA responsive element and expression of the Ah receptor-responsive g ene CYP1A1. LTr-1 was a competitive inhibitor of CYP1A1-dependent ethoxyres orufin-O-deethylase (EROD) activity. In summary, these results demonstrated that LTr-1, a major in vivo product of I3C, could inhibit the proliferatio n of both estrogen-dependent and -independent breast tumor cells and that L Tr-1 is an antagonist of estrogen receptor function and a weak agonist of A h receptor function. (C) 1999 Elsevier Science Inc.