ER, RXR, PPAR-γ, HMG-CoA reductase and HDAC as molecular targets for the chemoprevention of colorectal cancer.

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Recent advances have provided new and promising opportunities to identify molecular targets for the chemoprevention of colon cancer. Potentially new targets for chemopreventive agents development against colorectal cancer include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, estrogen receptor (ER), retinoic acid X receptor (RXR), peroxisome proliferator activating receptor (PPAR)-γ, and histone deacetylase (HDAC). Specific agents directed toward these targets include lipitor and lovastatin (HMG-CoA reductase), tamoxifen and raloxifen (ER), targretin (RXR), rosiglitazone (PPAR-γ), and valproic acid and SAHA (HDAC). We have studied the chemopreventive efficacy of tamoxifen, raloxifen, targretin, roglitazone, lovastatin, lipitor, valproic acid, and suberanilohydroxamic acid (SAHA) on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF). Seven week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing ∼40 and/or 80% of the maximum tolerated dose (MTD) of each agent. One week later, all animals were s.c. injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). At 15 weeks of age, all rats were killed and their colons were evaluated for ACF. Administration of tamoxifen, raloxifen, targretin, rosiglitazone, lipitor, lovastatin and valproic acid each significantly inhibited AOM-induced total colonic ACF (p<0.01-0.0001), including those with 4 or more crypts (p<0.01-0.0001, 26%-77%inhibition). Suppression of multicrypt foci based on chemopreventive efficacy occurred in the following order: HMG-CoA reductase inhibitors>ER agonists>PPAR-γ agonist>RXR-agonist>HDAC inhibitors. Studies are in progress to extend the chemopreventive potential of these agents using long-term colon tumor assays. [Supported by NCI-CN-25114 and CN-15122]