Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats.

The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K(m) and V(max)), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes.

Synergistic effects of a combination of dietary factors sulforaphane and (-) epigallocatechin-3-gallate in HT-29 AP-1 human colon carcinoma cells.

Purpose: The objective of this study was to investigate combinations of two chemopreventive dietary factors: EGCG 20 microM (or 100 microM) and SFN (25 microM) in HT-29 AP-1 human colon carcinoma cells.

Methods: After exposure of HT-29 AP-1 cells to SFN and EGCG, individually or in combination, we performed AP-1 luciferase reporter assays, cell viability assays, isobologram analyses, senescence staining, quantitative real-time PCR (qRT-PCR) assays, Western blotting, and assays for HDAC activity and hydrogen peroxide. In some experiments, we exposed cells to superoxide dismutase (SOD) or Trichostatin A (TSA) in addition to the treatment with dietary factors.

Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice.

This objective of this study was to investigate the toxicogenomics and the spatial regulation of global gene expression profiles elicited by endoplasmic reticulum (ER) stress inducer tunicamycin (TM) in mouse small intestine and liver as well as to identify TM-modulated nuclear factor-E2-related factor 2 (Nrf2)-dependent genes. Gene expression profiles were analyzed using 45,000 Affymetrix mouse genome 430 2.0 array and GeneSpring 7.

Pharmacogenomics of phenolic antioxidant butylated hydroxyanisole (BHA) in the small intestine and liver of Nrf2 knockout and C57BL/6J mice.

Purpose: The objective of this study was to investigate the pharmacogenomics and the spatial regulation of global gene expression profiles elicited by cancer chemopreventive agent butylated hydroxyanisole (BHA) in mouse small intestine and liver as well as to identify BHA-modulated nuclear factor-E2-related factor 2 (Nrf2)-dependent genes.

Methods: C57BL/6J (+/+; wildtype) and C57BL/6J/Nrf2(-/-; knockout) mice were administered a single 200 mg/kg oral dose of BHA or only vehicle. Both small intestine and liver were collected at 3 h after treatment and total RNA was extracted.

Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells.

In last couple of decades the use of natural compounds like flavonoids as chemopreventive agents has gained much attention. Our current study focuses on identifying chemopreventive flavonoids and their mechanism of action on human prostate cancer cells. Human prostate cancer cells (PC3), stably transfected with activator protein 1 (AP-1) luciferase reporter gene were treated with four main classes of flavonoids namely flavonols, flavones, flavonones, and isoflavones.

Pharmacogenomics of cancer chemopreventive isothiocyanate compound sulforaphane in the intestinal polyps of ApcMin/+ mice.

Sulforaphane (SFN) is an isothiocyanate that is present in widely consumed vegetables. Previous studies have shown that SFN is effective in preventing carcinogenesis induced by carcinogens in rodents. Recently it was found that SFN could also suppress the growth of intestinal polyps in the ApcMin/+ mouse.

Effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate Cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice.

Purpose: To investigate the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate cancer cells cultured in vitro or grown as tumors in immunodeficient mice.

Experimental Design: Human prostate cancer LNCaP cells in culture were treated with TPA alone or in combination with paclitaxel. NCr immunodeficient mice with well-established LNCaP tumors received i.

Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane, a natural product derived from cruciferous vegetable.

Sulforaphane (SFN) is an isothiocyanate that is present abundantly in widely consumed cruciferous vegetables and has a particularly high content in broccoli and cauliflower. It has been shown to be an effective inhibitor of some carcinogen-induced cancers in rodents. Here, we investigated the chemopreventive efficacy of SFN in the ApcMin/+ mouse model.

Differential expression of MUC genes in endometrial and cervical tissues and tumors.

Background: Mucin glycoprotein's are major components of mucus and are considered an important class of tumor associated antigens. The objective of this study was to investigate the expression of human MUC genes (MUC1, MUC2, MUC5B, MUC5AC and MUC8) in human endometrium and cervix, and to compare and quantitate the expression of MUC genes in normal and cancerous tissues.

Methods: Slot blot techniques were used to study the MUC gene expression and quantitation.

p53-independent G1 cell cycle arrest of human colon carcinoma cells HT-29 by sulforaphane is associated with induction of p21CIP1 and inhibition of expression of cyclin D1.

Isothiocyanate sulforaphane (SFN) is a potent cancer chemopreventive agent. We investigated the mechanisms underlying the anti-proliferative effects of SFN in the human colon carcinoma cell line, HT-29. We demonstrate that SFN inhibits the growth of HT-29 cells in a dose- and time-dependent manner.

Nrf2 Possesses a redox-insensitive nuclear export signal overlapping with the leucine zipper motif.

Basic leucine zipper (bZIP) protein Nrf2 is a key transcription factor mediating the antioxidant response. Under homeostatic conditions Nrf2 is anchored to cysteine-rich Keap1 and sequestered in the cytoplasm. When challenged with oxidative stress, Keap1 functions as a redox-sensitive switch and releases Nrf2.

Toxicogenomics of resveratrol in rat liver.

Resveratrol, a polyphenolic compound found in grape skin and peanuts has been shown to prevent many diseases including cardiovascular diseases and cancer. To better understand resveratrol's potential in vivo toxicity, we studied the dose response using cDNA stress arrays coupled with drug metabolizing enzymatic (DME) assays to investigate the expression of stress-responsive genes and Phase I and II detoxifying enzymes in rat livers. Male and female CD rats were treated with high doses of resveratrol (0.

Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals.

Garlic organosulfur compounds (OSCs) are recognized as a group of potential chemopreventive compounds. It is known that garlic OSCs can modulate drug metabolism systems, especially various phase II detoxifying enzymes, though the mechanism underlying their inductive effect on these enzymes remains largely unknown. In the present study, we investigated the transcriptional levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO1) genes, the reporter activity mediated by antioxidant response element (ARE), and the protein level of transcription factor nuclear factor E2-related factor 2 (Nrf2), after administration of three major garlic OSCs--diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS)--in human hepatoma HepG2 cells.

Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein.

Transcription factor NF-E2-related factor 2 (Nrf2) regulates the induction of Phase II detoxifying enzymes as well as anti-oxidative enzymes. In this study, we investigated the transactivation potential of different Nrf2 transactivation domain regions by using the Gal4-Nrf2 chimeras and Gal4-Luc reporter co-transfection assay system in HepG2 cells. The results indicated that chimera Gal4-Nrf2-(1-370), which contains the full transactivation domain showed very potent transactivation activity.

In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat.

Sulforaphane (SUL) is one member of the isothiocyanate class of cancer chemopreventive compounds that has been shown to be effective in blocking initiation and progression of carcinogenesis. Previously, many studies have shown that SUL can potently induce phase II detoxifying enzymes, which contributes to its chemopreventive functions. In this study, we used 4967 oligonucleotides microarray to assess the genes that are modulated by SUL in in vivo rat livers, as well as time course of expression of these genes.

Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane.

Sulforaphane (SFN) and its N-acetyl-L-cysteine (NAC) conjugate are effective inhibitors of tumorigenesis in animal models. These compounds induce the expression of the antioxidant response element (ARE)-related genes and cause apoptosis. We studied the role of reduced glutathione (GSH) in the activations of ARE-mediated gene expression, apoptosis, and the activation of c-Jun NH(2)-terminal kinase (JNK) in HepG2-C8 cells.

The roles of JNK and apoptotic signaling pathways in PEITC-mediated responses in human HT-29 colon adenocarcinoma cells.

Phenethyl isothiocyanate (PEITC) is a potential chemopreventive agent that is present naturally in widely consumed vegetables, especially in watercress. It has been extensively investigated for its anticancer activities against lung, forestomach and esophageal tumorigenesis. Here we investigated the pro-apoptotic effect of PEITC in HT-29 human colorectal carcinoma cell line, and the mechanism of apoptosis induced by PEITC.

Epigallocatechin-3-gallate-induced stress signals in HT-29 human colon adenocarcinoma cells.

Epigallocatechin-3-gallate (EGCG), a major component in green tea polyphenols, has been proven to suppress colonic tumorigenesis in animal models and epidemiological studies. As EGCG is retained in the gastrointestinal tract after oral administration, this pharmacokinetics property gives it the potential to function as a chemopreventive agent against colon cancer. In this study, human colorectal carcinoma HT-29 cells were treated with EGCG to examine the anti-proliferative and pro-apoptotic effects of EGCG, as well as the molecular mechanism underlying these effects.

Differential responses from seven mammalian cell lines to the treatments of detoxifying enzyme inducers.

Cell-based models have been used extensively in screening novel bioactive chemical entities. In this study, seven well-established mammalian cell lines, which have different origins, were utilized to compare their responses to the treatments of three detoxifying enzyme inducers, tert-butylhydroquinone (tBHQ), beta-naphthoflavone (beta-NF), and sulforaphane (SUL), which are potential chemopreventive compounds. The enzymatic activities of glutathione s-transferase (GST), NAD(P)H:quinone oxidoreductase (QR), aldehyde reductase (AR), and glutathione reductase (GR) were measured by kinetics methods using UV-Vis spectroscopy, and analyzed statistically by Student's t-test.