Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Epidemiological studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2-8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ (DCIS), or invasive ductal carcinoma (IDC) breast tissues. Within the supplement group, Ki-67 (p = 0.003) and HDAC3 (p = 0.044) levels significantly decreased in benign tissue. Pre-to-post-intervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (p = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention.

Conjugated linoleic acid (CLA) alters body composition in animal models, but few studies have examined the effects of CLA supplementation on body composition and clinical safety measures in obese humans. In the present study, we performed a randomized, double-blind, placebo-controlled trial to examine the changes in body composition and clinical laboratory values following CLA (50:50 ratio of cis-9, trans-11 and trans-10, cis-12 isomers) supplementation for 12 wk in otherwise healthy obese humans. Forty-eight participants (13 males and 35 females) were randomized to receive placebo (8 g safflower oil/d), 3.2 g/d CLA, or 6.4 g/d CLA for 12 wk. Changes in body fat mass and lean body mass were determined by dual-energy X-ray absorptiometry. Resting energy expenditure was assessed by indirect calorimetry. Clinical laboratory values and adverse-event reporting were used to monitor safety. Lean body mass increased by 0.64 kg in the 6.4 g/d CLA group (P < 0.05) after 12 wk of intervention. Significant decreases in serum HDL-cholesterol and sodium, hemoglobin, and hematocrit, and significant increases in serum alkaline phosphatase, C-reactive protein, and IL-6, and white blood cells occurred in the 6.4 g/d CLA group, although all values remained within normal limits. The intervention was well tolerated and no severe adverse events were reported, although mild gastrointestinal adverse events were reported in all treatment groups. In conclusion, whereas CLA may increase lean body mass in obese humans, it may also increase markers of inflammation in the short term.

Regulatory regions of the human genome can be modified through epigenetic processes during prenatal life to make an individual more likely to suffer chronic diseases when they reach adulthood. The modification of chromatin and DNA contributes to a larger well-documented process known as “programming” whereby stressors in the womb give rise to adult onset diseases, including cancer. It is now well known that death from ischemic heart disease is related to birth weight; the lower the birth weight, the higher the risk of death from cardiovascular disease as well as type 2 diabetes and osteoporosis. Recent epidemiological data link rapid growth in the womb to metabolic disease and obesity and also to breast and lung cancers. There is increasing evidence that “marked” regions of DNA can become “unmarked” under the influence of dietary nutrients. This gives hope for reversing propensities for cancers and other diseases that were acquired in the womb. For several cancers, the size and shape of the placenta are associated with a person’s cardiovascular and cancer risks as are maternal body mass index and height. The features of placental growth and nutrient transport properties that lead to adult disease have been little studied. In conclusion, several cancers have their origins in the womb, including lung and breast cancer. More research is needed to determine the epigenetic processes that underlie the programming of these diseases.

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