3,3Ј-Diindolylmethane (DIM, 1) is a major metabolite (spontaneously formed product in intragastric acid condition) of indole-3-carbinol (I3C, 2) which is a phytochemical expressed in brassica vegetables, including broccoli, brussels sprouts, kales and the cabbages, and has been thought to be associated with the anticancer/cancer chemopreventive activities of vegetable consumption.1) DIM (1) controls proliferation of various tumor cells, including cells of breast cancer, prostate cancer, ovary cancer, lung cancer and pancreatic cancer, by inducing G 1 /S arrest of the cell cycle and apoptosis.2) In addition, DIM (1) modulates metabolism of estrogen and testosterone, 3,4) which act as indigenous tumor promoters for several hormone-dependent cancers. DIM (1) is also reported to be a weak agonist for the arylhydrocarbon receptor (AhR) and blocks the effects of estrogens via inhibition of AhR-estrogen receptor cross talk.5) In addition, DIM (1) possesses other various activities, including immunomodulatory effect.6) All the experimental studies suggest that DIM (1) has incredible potential both for prevention and for treatment of cancer.Although the molecular basis of cancer chemopreventive and cancer chemotherapic effects of DIM (1) is unclear, effects of DIM (1) on cell differentiation would be one of candidate mechanisms underlying the biological activities elicited by DIM (1). In fact, Kim et al. recently reported that indirubin, another AhR agonist with a structure related to that of DIM (1), and its derivatives show enhancing effect on 1,25-dihydroxyvitamin D 3 (1,25-VD 3 )-and all-trans retinoic acid (ATRA)-induced cell differentiation of HL-60 leukemia cells.
7)Under such circumstances, we investigated the enhancing effect on chemically-induced HL-60 cell differentiation of DIM (1) and its derivatives in combination with various cell differentiation inducers, including ATRA, tamibarotene (Am80, 3), 1,25-VD 3 , 12-O-tetradecanoyl phorbol-13-acetate (TPA) and dimethyl sulfoxide (DMSO). All of these chemicals are known to induce terminal differentiation in leukemic cell lines, including HL-60 and U937 cells. ATRA and Am80 are therapeutic agents for acute promyelocytic leukemia (APL) and induce differentiation of HL-60 cells to mature granulocytes.8) On the other hand, 1,25-VD 3 and TPA have been established to induce differentiation of HL-60 cells to mature monocytes. 9) DMSO is another typical cell differentiation inducer.
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Results and DiscussionChemistry DIM (1), its derivatives (4-17), and isomers of DIM [2,2Ј-DIM (22) and 2,3Ј-DIM (25) Bunkyo-ku, Tokyo 113-0032, Japan. Received January 8, 2009; accepted February 19, 2009; published online February 24, 2009 3,3-Diindolylmethane (DIM, 1) and its derivatives have been prepared, and their enhancing effects on chemically-induced HL-60 cell differentiation were analyzed. Among the prepared compounds, IndDIM (12) showed the most potent enhancing effect on HL-60 cell differentiation induced by chemicals, including retinoids, 1,25-dihydroxyvitamin D 3 , 12-O-...
