tretinoin and ciglitazone

Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ(12,14)-Prostaglandin J(2) (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3-7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3-7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases.

Topics: Animals; Antigens; Cell Differentiation; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Epidermal Growth Factor; Fibroblast Growth Factor 2; Gene Expression; Glial Fibrillary Acidic Protein; Intermediate Filament Proteins; Mice; Nerve Tissue Proteins; Nestin; Neural Stem Cells; Oligodendroglia; PPAR gamma; Prostaglandin D2; Proteoglycans; Thiazolidinediones; Tretinoin; Tubulin

Nuclear retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs are potential candidates as drug target for cancer prevention and treatment. We investigated if the rexinoid 6-OH-11-O-hydroxyphenantrene (IIF) potentiates the antitumoral properties of PPARgamma ligands as ciglitazone and pioglitazone, on two colon cancer cell lines: HCA-7 and HCT-116. Drugs inhibited cell growth and induced apoptosis synergistically. The combination resulted in a decrease of cyclooxigenase-2, metalloproteinases-2 and -9 expression level and activity while PPARgamma, RXRgamma and tissue inhibitors of metalloproteinase-1 and -2 expression were increased. Finally, IIF potentiated PPAR transcriptional activity by enhancement of peroxisome proliferator response elements transactivation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Movement; Cell Proliferation; Cell Survival; Colonic Neoplasms; Cyclooxygenase 2; Dose-Response Relationship, Drug; Drug Synergism; HCT116 Cells; Humans; Ligands; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Pioglitazone; PPAR gamma; Response Elements; Retinoid X Receptor gamma; Thiazolidinediones; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transcriptional Activation; Tretinoin

Experimental data from in vitro and in vivo models indicate that peroxisome proliferator-activated receptor (PPAR) ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Thiazolidinediones such as ciglitazone (CGZ) constitute the most well-known synthetic ligands for PPARgamma. We previously reported a remarkable antitumor effect of the retinoid 6-OH-11-O-hydroxyphenantrene (IIF), synthetic retinoid X receptors (RXRs) agonist, on many cancer cell lines. Since PPARs bind to DNA as heterodimers with RXRs, in this study we investigated if IIF potentiates the antitumoral properties of the PPARgamma ligand CGZ in glioblastoma U87MG and melanoma G361 cells. Our results show that either IIF or CGZ inhibited cell growth and tissue invasion ability, but these properties were enhanced by using IIF and CGZ in combined treatment. Since matrix metalloproteinases (MMPs) play a major role in tumor cell invasion, we analyzed the effect of IIF and CGZ on MMP2 and MMP9 activity and expression. The addition of IIF to CGZ resulted in a decrease of MMP2 and MMP9 expression and activity, higher than when each agent was used alone. Furthermore, treatment with IIF and/or CGZ enhanced PPARgamma expression but both agents in combined treatment caused the maximum efficiency. Finally, we demonstrated that IIF can potentiate PPARgamma trascriptional activity induced by CGZ, by evaluation of peroxisome proliferator-responsive element transactivation. In conclusion, these findings suggest that the RXR selective retinoid IIF, in combination with the PPARgamma ligand CGZ, may provide a therapeutic advantage in cancer treatment.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Drug Synergism; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasms; PPAR gamma; Retinoid X Receptors; Thiazolidinediones; Tretinoin

The involvement of peroxisome proliferator-activated receptors (PPARs) in the cancer cell elimination through apoptosis is a generally accepted fact. However, some reports indicate that the activation of PPARgamma is directly responsible for carcinogenesis. Caco-2 cells, a human adenocarcinoma cells, were used as a model of colon cancer. Cell cultures (5 x 10(6) cell per dish) were pretreated for 24 h with PPAR gamma agonists ciglitazone (CI, 1 x 10(-6)M) and retinoic acid (RA, 1 x 10(-6)M) and part of the cultures were subsequently subjected to gamma-radiation (photons) with therapeutic dose of 2,5 Gy. Total cellular RNA and proteins (cytoplasmic and nuclear) were isolated 24h after cultures irradiation or 48 h after stimulation in the non irradiated part of experiment to preserve the equal growth time for all samples. gamma-Irradiation of the cells abolished nuclear translocation of PPARgamma under its agonists treatment and preserved PPARgamma in the cytoplasmic pool. But it did not affect the HSP 70 expression in response to ciglitazone and retinoic acid. Moreover, combined gamma-irradiation and CI/RA treatment of the cells changed the equilibrium between Bax and Bcl-2 mRNA to anti apoptotic state with increased expression of Bcl-2 and almost abolished expression of Bax. In conclusion, this paper provides an evidence for the anti-apoptotic action of PPARgamma agonists used along with the gamma-radiation. Moreover, it shows that the up-regulated HSP70, in response to PPARgamma agonists in gamma-irradiated cultures promotes cell survival.

Topics: Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caco-2 Cells; Colonic Neoplasms; Gamma Rays; Gene Expression Regulation, Neoplastic; HSP70 Heat-Shock Proteins; Humans; Polymerase Chain Reaction; PPAR gamma; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazolidinediones; Tretinoin

Insulin resistance is the failure of insulin to stimulate the transport of glucose into its target cells. A highly regulatable supply of glucose is important for cardiomyocytes to cope with situations of metabolic stress. We recently observed that isolated adult rat cardiomyocytes become insulin resistant in vitro. Insulin resistance is combated at the whole body level with agonists of the nuclear receptor complex peroxisome proliferator-activated receptor gamma (PPARgamma)/retinoid X receptor (RXR). We investigated the effects of PPARgamma/RXR agonists on the insulin-stimulated glucose transport and on insulin signaling in insulin-resistant adult rat cardiomyocytes. Treatment of cardiomyocytes with ciglitazone, a PPARgamma agonist, or 9-cis retinoic acid (RA), a RXR agonist, increased insulin- and metabolic stress-stimulated glucose transport, whereas agonists of PPARalpha or PPARbeta/delta had no effect. Stimulation of glucose transport in response to insulin requires the phosphorylation of the signaling intermediate Akt on the residues Thr308 and Ser473 and, downstream of Akt, AS160 on several Thr and Ser residues. Phosphorylation of Akt and AS160 in response to insulin was lower in insulin-resistant cardiomyocytes. However, treatment with 9-cis RA markedly increased phosphorylation of both proteins. Treatment with 9-cis RA also led to better preservation of microtubules in cultured cardiomyocytes. Disruption of microtubules in insulin-responsive cardiomyocytes abolished insulin-stimulated glucose transport and reduced phosphorylation of AS160 but not Akt. Metabolic stress-stimulated glucose transport also involved AS160 phosphorylation in a microtubule-dependent manner. Thus, the stimulation of glucose uptake in response to insulin or metabolic stress is dependent in cardiomyocytes on the presence of intact microtubules.

Topics: Alitretinoin; AMP-Activated Protein Kinase Kinases; Animals; Cells, Cultured; Cytoskeleton; Glucose; Glucose Transporter Type 4; Insulin; Insulin Resistance; Male; Microtubules; Myocytes, Cardiac; Phenoxyacetates; PPAR gamma; Protein Kinases; Pyrimidines; Rats; Rats, Sprague-Dawley; Retinoid X Receptors; Signal Transduction; Thiazolidinediones; Tretinoin

Melanoma represents one of the most rapidly metastasizing, hence deadly tumors due to its high proliferation rate and invasiveness, characteristics of undifferentiated embryonic tissues. Given the absence of effective therapy for metastatic melanoma, understanding more fully the molecular mechanisms underlying melanocyte differentiation may provide opportunities for novel therapeutic intervention. Here we show that in mouse melanoma S91 cells activation of the peroxisome proliferator activated receptor (PPAR) gamma induces events resembling differentiation, such as growth arrest accompanied by apoptosis, spindle morphology and enhanced tyrosinase expression. These events are preceded by an initial transient increase in expression from the Microphthalmia-associated transcription factor gene, (MITF) promoter, whereas exposure to a PPAR gamma ligand- ciglitazone that exceeds 8 h, causes a gradual decrease of MITF, until by 48 h MITF expression is substantially reduced. Beta-catenin, an MITF transcriptional activator, shows a similar pattern of decline during ciglitazone treatment, consistent with previous reports that activated PPAR gamma inhibits the Wnt/beta-catenin pathway through induction of beta-catenin proteasomal degradation. We suggest that the PPAR gamma-mediated beta-catenin down-regulation is likely to be responsible for changes in MITF levels. The data suggest that PPAR gamma, besides its well-established role in mesenchymal cell differentiation towards adipocytes, might regulate differentiation in the melanocytic lineage.

Topics: Alitretinoin; Animals; Antigens, Differentiation; Antineoplastic Agents; beta Catenin; Blotting, Western; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Shape; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Melanocytes; Melanoma; Mice; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Phenotype; PPAR gamma; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Thiazolidinediones; Tretinoin; Up-Regulation

The liver X receptors (LXRalpha and LXRbeta), ligand-activated transcription factors, belong to the superfamily of nuclear hormone receptors and have been shown to play a major role in atherosclerosis by modulating cholesterol and triglyceride metabolism. In this report, we describe a novel LXR target, the adipocyte fatty acid binding protein (aP2), which plays an important role in fatty acid metabolism, adipocyte differentiation and atherosclerosis. While LXR agonists induce aP2 mRNA expression in human monocytes (THP-1 cells) and macrophages in a time- and concentration-dependent manner, they have no effect on aP2 expression in human adipocytes. The increase in aP2 mRNA level was additive when THP-1 cells were treated with LXR and PPARgamma agonists. Also, an RXR agonist induced aP2 expression in these cells. While no additive effect was observed with LXR and RXR agonists, additive effects were observed with RXR and PPARgamma agonists. GW9662, a potent PPARgamma antagonist, inhibited PPARgamma-induced aP2 expression without affecting LXR-mediated aP2 expression indicating the induction is mediated directly through LXR activation. Analysis of human aP2 promoter revealed a potential LXR response element (LXRE). Gel shift data showed that the LXRalpha/RXRalpha heterodimer bound to the LXRE motif in aP2 promoter in vitro in a sequence-specific manner. Deletion and mutation analyses of the proximal aP2 promoter confirm that this is a functional LXRE. These data indicate for the first time that human macrophage aP2 promoter is a direct target for the regulation by LXR/RXR heterodimers.

Topics: 5' Flanking Region; Adipocytes; Alitretinoin; Base Sequence; Binding Sites; Cell Differentiation; Cell Line; Dimerization; DNA-Binding Proteins; Drug Synergism; Fatty Acid-Binding Proteins; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Liver X Receptors; Macrophages; Molecular Sequence Data; Orphan Nuclear Receptors; PPAR gamma; Protein Binding; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Response Elements; Sequence Deletion; Sulfonamides; Thiazolidinediones; Tretinoin

Peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptors (RARs) have been a focus in chemotherapy for human cancers. The tumor suppressor PTEN plays a pivotal role in the growth of human cancer cells. We investigated whether costimulation of PPARgamma and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells. We found that overexpression of PTEN with the adenoviral vector Ad/PTEN caused growth arrest at the G1 phase of the cell cycle of HL-60 cells. HL-60 cells treated with either a PPARgamma ligand (ciglitazone) or a RAR ligand (all-trans retinoic acid [ATRA]) up-regulated PTEN in HL-60 cells. The 2 compounds in combination showed synergistic effects on PTEN expression at the protein and messenger RNA levels. Moreover, the combination of ciglitazone and ATRA synergistically reduced cell growth rates and cell cycle arrest at the G1 phase. Our results suggest that, PPARgamma and RAR play an important role in controlling the growth of leukemia cells via the up-regulation of PTEN.

Topics: Cell Cycle; HL-60 Cells; Humans; PPAR gamma; PTEN Phosphohydrolase; Receptors, Retinoic Acid; Thiazolidinediones; Tretinoin; Up-Regulation

The activation of the peroxisome proliferator-activated receptor gamma (PPAR gamma) that forms heterodimers with retinoid X receptors (RXRs) elicits an antineoplastic effect on colorectal cancer. It was previously reported that the accumulation of the non-functional phosphorylated form of RXR alpha (p-RXR alpha) interfered with its signalling and promoted the growth of hepatoma cells. In this study the effects of p-RXR alpha on the ability of RXR alpha and PPAR gamma ligands to inhibit growth in colon cancer cells was examined.. The effects of the combination of the PPAR gamma ligand ciglitazone and the RXR alpha lignad 9-cis-retinoic acid (RA) on inhibition of cell growth in Caco2 human colon cancer cells which express high levels of p-RXR alpha protein were examined.. The RXR alpha protein was phospholylated and also accumulated in human colon cancer tissue samples as well as human colon cancer cell lines. When the phosphorylation of RXR alpha was inhibited by the MEK inhibitor PD98059 or by transfection with a point-mutated RXR alpha, which mimicked the unphosphorylated form, the combination of 9-cisRA and ciglitazone synergistically inhibited the cell growth and induced apoptosis. The combined treatment with these agents also caused a decrease in the expression levels of both cyclo-oxygenase-2 (COX-2) and c-Jun proteins and mRNAs. Reporter assays indicated that this combination induced the transcriptional activity of the peroxisome proliferator-responsive element promoter and also inhibited that of the AP-1 promoter.. A malfunction of RXR alpha due to phosphorylation is associated with colorectal cancer. Therefore, the inhibition of phosphorylation of RX R alpha and the activation of the RXR-PPAR gamma heterodimer by their respective ligands may be useful in the chemoprevention and/or treatment of colorectal cancer.

Topics: Caco-2 Cells; Colonic Neoplasms; Drug Synergism; Female; Growth Inhibitors; Humans; Male; Phosphorylation; PPAR gamma; Retinoid X Receptor alpha; Thiazolidinediones; Tretinoin

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a critical albeit poorly defined role in the development and progression of several cancer types including those of the breast, colon, and lung. A PPAR response element (PPRE) reporter assay was utilized to evaluate the selective transactivation of PPARgamma in 10 different cell lines including normal mammary epithelial, breast, lung, and colon cancer cells. Cells were treated with one of four compounds including rosglitizone (Ros), ciglitizone (Cig), 15-deoxy-Delta(12,14)-prostaglandin J2 (PGJ2), or GW 9662 (GW). We observed differences in transactivation between cell lines from different tissue origin, across cell lines from a single tissue type, and selective modulation of PPARgamma within a single cell line by different ligands. Interestingly, GW, a PPARgamma antagonist in adipocytes, enhanced PPRE reporter activation in normal mammary epithelial cells while it had virtually no effect in any of the cancer cell lines tested. Within each cancer type, individual cell lines were found to respond differently to distinct PPARgamma ligands. For instance, Ros, Cig, and PGJ2 were all potent agonist of PPARgamma transactivation in lung adenocarcinoma cell lines while these same ligands had no effect in squamous cell or large cell carcinomas of the lung. Message levels of PPARgamma and retinoid X receptor alpha (RXRalpha) in the individual cell lines were quantitated by real time-polymerase chain reaction (RT-PCR). The ratio of PPARgamma to RXRalpha was predictive of how cells responded to co-treatment of Ros and 9-cis-retinoic acid, an RXRalpha agonist, in two out of three cell lines tested. These data indicate that PPARgamma can be selectively modulated and suggests that it may be used as a therapeutic target for individual tumors.

Topics: Alitretinoin; Anilides; Breast Neoplasms; Caco-2 Cells; Cell Line, Tumor; Colonic Neoplasms; Female; Gene Expression Regulation, Neoplastic; Genes, Reporter; HT29 Cells; Humans; Ligands; Lung Neoplasms; PPAR gamma; Prostaglandin D2; Retinoid X Receptor alpha; RNA, Messenger; Rosiglitazone; Thiazolidinediones; Transfection; Tretinoin

Multiple myeloma is essentially an incurable malignancy and it is therefore of great interest to develop new therapeutic approaches. We previously reported that human B cell-lymphomas express the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are killed by PPARgamma ligands. Herein, we investigate the therapeutic potential of PPARgamma ligands for multiple myeloma. The human multiple myeloma cell lines ANBL6 and 8226 express PPARgamma mRNA and protein. The PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone, induced multiple myeloma cell apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, loss of mitochondrial membrane potential, and caspase activation. Importantly, the ability of PPARgamma ligands to kill both multiple myeloma cell lines was not abrogated by Interleukin-6 (IL-6), a multiple myeloma growth survival factor. Finally, the RXR ligand 9-cis retinoic acid (9-cis RA) in combination with PPARgamma ligands greatly enhanced multiple myeloma cell killing. These new findings support that PPARgamma ligands may represent a novel therapy for multiple myeloma.

Topics: Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Enzyme Activation; Humans; Immunohistochemistry; Immunologic Factors; In Situ Nick-End Labeling; Interleukin-6; Ligands; Membrane Potentials; Mitochondria; Multiple Myeloma; PPAR gamma; Prostaglandin D2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Tretinoin

This study was designed to investigate whether nuclear receptor agonists can be used as potential differentiation therapy agents for human osteosarcoma.. Four osteosarcoma cell lines (143B, MNNG/HOS, MG-63, and TE-85) were treated with proliferator-activated receptor (PPAR)gamma agonists, troglitazone and ciglitazone, and a retinoid X receptor (RXR) ligand, 9-cis retinoic acid. The proliferation and induction of apoptosis in the treated cells were assessed, as was the induction of alkaline phosphatase, a differentiation marker of osteoblasts.. The expression of PPARgamma was readily detected in all tested osteosarcoma lines. On treatment with the PPARgamma and RXR ligands, all four osteosarcoma lines exhibited a significantly reduced proliferation rate and cell viability. Among the four lines, 143B and MNNG/HOS were shown to be more sensitive to ligand-induced apoptosis, as demonstrated by the Crystal Violet and Hoechst staining assays. Of the three tested ligands, troglitazone was shown to be the most effective in inducing cell death, followed by 9-cis retinoic acid. Moreover, a strong synergistic effect on the induction of cell death was observed when both troglitazone and 9-cis retinoic acid or ciglitazone and 9-cis retinoic acid were administered to osteosarcoma cells. Troglitazone was shown to effectively induce alkaline phosphatase activity, a well-characterized hallmark for osteoblastic differentiation.. Our findings suggest that PPARgamma and/or RXR ligands may be used as efficacious adjuvant therapeutic agents for primary osteosarcoma, as well as potential chemopreventive agents for preventing the recurrence and metastasis of osteosarcoma after the surgical removal of the primary tumors.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Division; Chromans; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Osteosarcoma; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; RNA, Neoplasm; Thiazoles; Thiazolidinediones; Time Factors; Transcription Factors; Tretinoin; Troglitazone; Tumor Cells, Cultured

We investigated whether and how could various modulators of arachidonic acid metabolism affect apoptosis induced by tumour necrosis factor-alpha (TNF-alpha) in human myeloid leukaemia HL-60 cells. These included arachinonyltrifluoromethyl ketone (AACOCF3; cytosolic phospholipase A2 inhibitor), indomethacin (cyclooxygenase inhibitor), MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethyl propanoic acid; 5-lipoxygenase-activating protein inhibitor), nordihydroguaiaretic acid (general lipoxygenase inhibitor), and arachidonic acid itself. Incubation of HL-60 cells with nordihydroguaiaretic acid resulted in apoptosis and it was characterised by mitochondria membrane depolarisation, release of cytochrome c from mitochondria into cytosol and activation of caspase-3. Indomethacin and nordihydroguaiaretic acid synergistically potentiated TNF-alpha-induced apoptosis, while arachidonic acid, AACOCF3 and MK-886 did not modulate its effects. Furthermore, indomethacin potentiated apoptosis in cells treated with a differentiating agent, all-trans retinoic acid, which induces resistance to TNF-alpha. However, the observed effects were probably not associated either with the cyclooxygenase- or lipoxygenase-dependent activities of indomethacin and nordihydroguaiaretic acid, respectively. Since indomethacin may reportedly activate peroxisome proliferator-activated receptors (PPARs), the effects of specific ligands of PPARs on apoptosis were studied as well. It was found that selective PPARs ligands had no effects on TNF-alpha-induced apoptosis. The findings suggest that arachidonic acid metabolism does not play a key role in regulation of apoptosis induced by TNF-alpha in the present model. Nevertheless, our data raise the possibility that indomethacin could potentially be used to improve the treatment of human myeloid leukaemia.

Topics: Apoptosis; Arachidonic Acid; Caspase 3; Caspases; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytochrome c Group; Cytosol; Dose-Response Relationship, Drug; Drug Synergism; HL-60 Cells; Humans; Indomethacin; Isoenzymes; Masoprocol; Membrane Proteins; Peroxisome Proliferators; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin; Tumor Necrosis Factor-alpha

The gamma isoform of the peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that regulates adipocyte differentiation. Recently it has been shown to be expressed in human colonic mucosa and cancer, but its role in colon carcinogenesis and progression is still unclear. We demonstrate that activation of PPARgamma by ciglitazone (cig), a selective PPARgamma ligand, induces HT-29 human colon cancer cells to undergo apoptosis. Treatment with cig also down-regulates expression of cyclooxygenase-2 (COX-2) protein. Simultaneous exposure of cells to cig and 9-cis-retinoic acid (9-cis-RA), a ligand for retinoid X receptor, results in an increased apoptotic effect and increased inhibition of COX-2 expression, compared with cells treated with either cig or 9-cis-RA alone. As COX-2 is overexpressed in human colon cancer and has been implicated in augmenting invasiveness and tumorigenecity, the ability of PPARgamma activation to decrease COX-2 expression and induce apoptosis suggests that the PPARgamma pathway may be considered as a therapeutic target for colon cancer.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Cell Division; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; DNA Fragmentation; Down-Regulation; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Genes, cdc; HT29 Cells; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin

Release of arachidonic acid from rat liver cells is stimulated after a 6-hour incubation with 9-cis retinoic acid, all trans retinoic acid, the selective peroxisome proliferator-activated receptor-gamma synthetic thiazolidinedione, ciglitazone, the cyclopentenones, 15-deoxy-Delta(12,14) PGJ2 and PGA1 and the non-steroidal anti-inflammatory drugs, celecoxib and indomethacin. The rates of the release stimulated by 15-deoxy-Delta(12,14) PGJ2 differ from those observed with celecoxib. Arachidonic acid release by9-cis retinoic acid in the presence of either ciglitazone or trans retinoic acid is synergistic. It is additive in the presence of celecoxib. Cycloheximide and actinomycin inhibit the release of arachidonic acid stimulated by 15-deoxy-Delta(12,14) PGJ2 but not by celecoxib. The findings indicate that agonists of the peroxisome proliferator-activated receptor-gamma and retinoic acid receptors stimulate the release of arachidonic acid. The mechanisms involved may differ in the cases of 15-deoxy-Delta(12,14) PGJ2 and celecoxib.

Topics: Alitretinoin; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Celecoxib; Cell Line; Cycloheximide; Dactinomycin; Dose-Response Relationship, Drug; Drug Synergism; Indomethacin; Kinetics; Liver; Prostaglandin D2; Prostaglandins A; Pyrazoles; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Sulfonamides; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is activated by 15-deoxy-delta(12,14) prostaglandin J2 (15d-PGJ2), anti-diabetic thiazolidinediones and several non-steroidal anti-inflammatory drugs (NSAIDs). In rat glial cells, lipopolysaccharide and interferon-gamma (LPS/IFN-gamma) induced expression of both inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1). PPARgamma activators inhibited iNOS expression by LPS and IFN-gamma. However, PPARgamma activator alone induced HO-1 expression and further enhanced LPS/IFN-gamma-induced HO-1 expression. These results suggest that activation of PPARgamma negatively regulate iNOS expression and positively regulates HO-1 expression in glial cells.

Topics: Alitretinoin; Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Cells, Cultured; Dinoprostone; Enzyme Induction; Gene Expression Regulation, Enzymologic; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Interferon-gamma; Lipopolysaccharides; Neuroglia; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Prostaglandin D2; Pyrimidines; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin