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PubMed2006

Peroxisome proliferator-activated receptor gamma-independent repression of prostate-specific antigen expression by thiazolidinediones in prostate cancer cells.

In light of the potential use of the thiazolidinedione family of peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists in prostate cancer treatment, this study assessed the mechanism by which these agents suppress prostate-specific antigen (PSA) secretion in prostate cancer cells. Two lines of evidence indicate that the effect of thiazolidinediones on PSA down-regulation is independent of PPARgamma activation. First, this thiazolidinedione-mediated PSA down-regulation is structure-specific irrespective of the relative PPARgamma agonist potency. Second, the PPARgamma-inactive analogs of troglitazone and ciglitazone [Delta2TG (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-thiazolidine-2,4-dione) and Delta2CG (5-[4-(1-methyl-cyclohexylmethoxy)-benzylidene]-thiazolidine-2,4-dione), respectively] exhibit higher potency than the parent compound in inhibiting dihydrotestosterone (DHT)-stimulated PSA secretion. Although 10 microM troglitazone and Delta2TG significantly inhibit PSA secretion, they do not alter the expression level of androgen receptor (AR) or interfere with DHT-activated nuclear translocation of AR. However, reporter gene and chromatin immunoprecipitation studies indicate that troglitazone and Delta2TG block AR recruitment to the androgen response elements within the PSA promoter. Thus, this study raises the question of whether the ability of oral troglitazone to reduce PSA levels in prostate cancer patients is therapeutically relevant. A major concern is that the concentration for troglitazone to mediate antitumor effects is severalfold higher than that of PSA down-regulation, which is difficult to attain at therapeutic doses. Nevertheless, it is noteworthy that troglitazone and Delta2TG at high doses were able to inhibit AR expression. From a translational perspective, separation of PPARgamma agonist activity from AR down-regulation provides a molecular basis to use troglitazone as a platform to design AR-ablative agents.

Animals↗

PubMed2004

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans.

AIMS/HYPOTHESIS: Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding. METHODS: Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined. RESULTS: Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells. CONCLUSIONS/INTERPRETATION: Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.

Animals↗

PubMed2000

Acute hemodynamic effects of insulin-sensitizing agents in isolated perfused rat hearts.

Troglitazone has direct effects on the hemodynamics of the heart. We investigated the effects of other insulin-sensitizing agents (rosiglitazone, pioglitazone and JTT-501 (4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3, 5-isoxazolidinedione)) on the hemodynamics of the heart using isolated perfused rat hearts. Rosiglitazone significantly decreased heart rate and coronary perfusion pressure, and increased peak isovolumic left ventricular pressure, peak rate of rise of left ventricular pressure and peak rate of fall of left ventricular pressure. The effects of rosiglitazone, however, were milder than those of troglitazone. Neither pioglitazone nor JTT-501 had any effect on the heart. D-alpha-tocopherol, a structural component of troglitazone, did not exert any effect on the heart. The coronary vasorelaxant effect of troglitazone and rosiglitazone was significantly suppressed by indomethacin, but not by N(omega)-nitro-L-arginine methyl ester. In conclusion, only rosiglitazone, as well as troglitazone, exerted positive inotropic, positive lusitropic, negative chronotropic, and coronary vasorelaxant effects on the heart. The coronary vasorelaxant effect of troglitazone and rosiglitazone was mediated by prostaglandin production.

Animals↗

PubMed1998

Insulin action enhancement normalizes brachial artery vasoactivity in patients with peripheral vascular disease and occult diabetes.

PURPOSE: Brachial artery vasoactivity (BAVA) evaluation is a reliable, noninvasive method of assessing arterial endothelial function in vivo. We previously have shown that patients with peripheral vascular disease (PVD) and occult diabetes have abnormal BAVA results when fasting and after oral glucose intake during oral glucose tolerance test (OGTT). Troglitazone is an oral hypoglycemic agent that enhances the action of insulin. The effect of troglitazone on BAVA in patients with occult diabetes and PVD is not known. METHODS: Patients with PVD, normal fasting glucose levels, and abnormal OGTT results were identified. With a duplex ultrasound scan, BAVA was evaluated by measuring the brachial artery (BA) flow (in millimeters per minute) before and after 5 minutes of BA occlusion during fasting and at 30 minutes, 1 hour, and 2 hours after the administration of 75 g of glucose during OGTT. Troglitazone therapy (400 mg/day) was begun, and the BAVA evaluation was repeated after 2 and 4 months. These results were compared with the results of the control group who had normal fasting glucose levels, normal OGTT results, and no evidence of PVD. A paired t test was used to compare the BA flow before and after BA occlusion, with a P value of less than.05 considered significant. RESULTS: The control group had a normal hyperemic response with a significantly increased BA flow after 5 minutes of BA occlusion during fasting and at all stages of the OGTT. The occult diabetic group had an abnormal response to hyperemia before the treatment with troglitazone and showed little change in flow after BA occlusion. After 2 months of troglitazone therapy, BAVA results improved after oral glucose intake but not during fasting. After 4 months, BAVA results normalized both while fasting and after oral glucose intake during the OGTT. CONCLUSION: Patients with occult diabetes and PVD have impaired BAVA, which normalizes after treatment with troglitazone. Insulin-action enhancers may slow the progression of PVD in patients with diabetes by improving endothelial cell function. Agents that are aimed at enhancing the action of insulin may have an advantage over the other traditional therapies for diabetes.

Aged↗

PubMed2002

Ligands of peroxisome proliferator-activated receptor-gamma induce apoptosis in AR42J cells.

INTRODUCTION: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor that controls growth, differentiation, and inflammation in different tissues. Roles of PPAR-gamma activation in pancreatic acinar cells are poorly characterized. AIMS: To examine the effects of PPAR-gamma activation on the induction of apoptosis in rat pancreatic AR42J cells. METHODOLOGY: AR42J cells were treated with ligands of PPAR-gamma, and induction of apoptosis was evaluated by cell viability, DNA-fragmentation, and flow cytometry. RESULTS: Treatment of the cells with ligands of PPAR-gamma (15-deoxy-open triangle12,14-prostaglandin J2 or troglitazone) induced apoptosis in a dose-dependent manner. Troglitazone-induced apoptosis was not blocked by inhibitors of caspases (acetyl-DEVD-aldehyde and benzoyloxycarbonyl-VAD-fluoromethylketone). Troglitazone induced the expression of pancreatitis-associated protein-1 and clusterin mRNAs. Troglitazone activated c-Jun NH2-terminal kinase/stress-activated protein kinase, but inhibited the activation of extracellular signal-regulated kinases 1/2. Troglitazone did not activate NF-kappaB, suggesting a role of NF-kappaB-independent pathways. In AR42J cells and isolated pancreatic acini, PPAR-gamma gene and protein were detected. In addition, troglitazone increased the PPAR-dependent transcriptional activity, suggesting that PPAR-gamma is functional in AR42J cells. CONCLUSION: These results indicate that activation of PPAR-gamma induces apoptosis in AR42J cells and imply that PPAR-gamma may be a potential therapeutic target of pancreatic inflammation, because of its anti-inflammatory effects in addition to its proapoptotic effects.

Amino Acid Chloromethyl Ketones↗

PubMed2002

Thiazolidinedione derivatives as novel therapeutic agents to prevent the development of chronic pancreatitis.

INTRODUCTION: Thiazolidinedione derivatives are known to be novel insulin-sensitizing agents and ligands of a nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). Recently, ligands of PPARgamma have been shown to modulate proinflammatory cytokine production and NF-kappaB activation. AIM: To show that thiazolidinedione derivatives interfere with the development of chronic pancreatitis. METHODOLOGY: Rat chow containing 0.2% troglitazone was administered from 1 month to 7 months of age in WBN/Kob rats with spontaneous chronic pancreatitis. Morphologic evaluation of the pancreas was performed at 4 months and 7 months of age. Pancreas weight, protein, amylase, and insulin contents also were determined. Changes of cytokine levels were detected by enzyme-linked immunosorbent assay or semiquantitative reverse transcription-polymerase chain reaction. Localization and expression of PPARgamma in the pancreas and isolated peritoneal macrophages were examined by immunohistochemical study. RESULTS: Administration of troglitazone reduced the severity of morphologic pancreatic damage including inflammatory cell infiltration, and fibrosis markedly improved by the administration of troglitazone. Further, troglitazone was able to prevent the decrease in amylase content and pancreas atrophy that were observed in WBN/Kob rats. Serum IL-8 levels and TNF-alpha mRNA levels in the pancreas were significantly elevated in WBN/Kob rats, and these were dramatically attenuated by troglitazone. Peritoneal macrophages isolated from normal rats expressed PPARgamma at low levels, whereas those from WBN/Kob rat abundantly expressed PPARgamma. CONCLUSION: Troglitazone prevented the progression of pancreatic inflammatory process in an animal model of chronic pancreatitis. Macrophages may be one of the targets of the PPARgamma ligand to attenuate the severity of chronic pancreatitis, partially mediated by the inhibition of proinflammatory cytokine gene expression.

Amylases↗

PubMed2003

Peroxisome proliferator-activated receptor-gamma agonists modulate macrophage activation by gram-negative and gram-positive bacterial stimuli.

Bacterial products, such as lipopolysaccharide (LPS) or heat-killed Escherichia coli (EC), and heat-killed Staphylococcus aureus (SA) are potent activators of macrophages (MØ). When stimulated by these bacterial components, MØ produce inflammatory mediators, such as nitric oxide (NO) and thromboxane (Tx) B(2). Bacterial mediator production is preceded by the activation of various signal transduction pathways. Agonists that activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been shown to block MØ mediator production by LPS and other stimuli. However, very little is known about the effects of PPARgamma agonists on SA- or EC-induced MØ activation. Therefore, we investigated whether the PPARgamma agonists 15-deoxy-Delta12,14 prostaglandin J(2) (15-PGJ(2)) and troglitazone block LPS-, EC-, or SA-induced mediator production. Rat peritoneal MØ were stimulated with LPS, EC, or SA (10 microg/mL) with or without increasing concentrations (0.1 to 10 microM) of each PPARgamma agonist and NO and TxB(2) production were measured. 15-PGJ(2) decreased LPS-, EC-, and SA-induced NO and TxB(2) production. However, troglitazone only inhibited the production of TxB(2) by each stimuli. In parallel studies, the effects of PPARgamma agonists on signaling pathways were evaluated. Rat peritoneal MØ were pretreated for 1 h with 15-PGJ(2) or troglitazone (1 or 10 microM) and then stimulated for 40 min with LPS, EC, or SA (10 microg/mL). Western blot analysis demonstrated that 15-PGJ(2) significantly inhibited LPS-, EC-, and SA-induced ERK (1/2) activation and blocked IkappaBalpha degradation. Troglitazone had no significant effect on either signaling protein. The data demonstrate that although both 15-PGJ(2) and troglitazone are considered PPARgamma agonists, they differentially affect mediator production and cell signaling events. PPARgamma-independent effects of 15-PGJ(2) may contribute to its more potent anti-inflammatory effects compared with troglitazone.

Animals↗

PubMed2002

A ligand for peroxisome proliferator activated receptor gamma inhibits cell growth and induces apoptosis in human liver cancer cells.

BACKGROUND AND AIMS: Induction of apoptosis of cancer cells through ligands of nuclear hormone receptors (NHRs) is a new approach in cancer therapy. Recently, one of the NHRs, peroxisome proliferator activated receptor gamma (PPARgamma), has been shown to influence cell growth in certain cancer cells although its effect on hepatocellular carcinoma (HCC) has not been analysed. METHODS: Experiments were conducted using three human liver cancer cell lines, PLC/PRF/5, Hep G2 and HuH-7, in vitro. These cells were exposed to troglitazone, a synthetic ligand for PPARgamma, and the effects on cell growth were analysed. RESULTS: Expression of PPARgamma mRNA was detected in all three liver cancer cell lines. Activation of PPARgamma by troglitazone caused a marked growth inhibition in a dose dependent manner in three hepatoma cell lines. The DNA fragmentation ELISA assay and Hoechst 33258 staining revealed that the growth inhibitory effect by adding troglitazone was due to apoptosis of PLC/PRF/5, which strongly expressed PPARgamma. Troglitazone also induced activation of the cell death protease, caspase 3, but not caspase 8, in PLC/PRF/5 cells. However, expression levels of antiapoptotic factor bcl-2 and apoptosis inducing factor bax were not affected. CONCLUSION: Our study showed that PPARgamma was expressed in human liver cancer cells and that the ligand for PPARgamma, troglitazone, inhibited the growth of these cells by inducing apoptosis through caspase 3 activation, indicating that troglitazone could be potentially useful as an apoptosis inducer for the treatment of HCC.

Antineoplastic Agents↗

PubMed2002

PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts.

This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-gamma expression induced by 10 microg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-alpha mRNA expression was not modified. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 microM) only inhibited iNOS mRNA expression (-50%). 15d-PGJ(2) decreased LPS-induced interleukin (IL)-1 beta (-25%) and tumor necrosis factor (TNF)-alpha (-40%) expression. Interestingly, troglitazone strongly decreased TNF-alpha expression (-50%) but had no significant effect on IL-1 beta expression. 15d-PGJ(2) was able to inhibit DNA-binding activity of both nuclear factor (NF)-kappa B and AP-1. Troglitazone had no effect on NF-kappa B activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ(2) and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-alpha and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-gamma ligands and underline different mechanisms of action of 15d-PGJ(2) and troglitazone in synovial fibroblasts.

Animals↗

PubMed2001

Hepatotoxicity with thiazolidinediones: is it a class effect?

Decreased insulin sensitivity plays a major role in various human diseases. particularly type 2 diabetes mellitus, and is associated with a higher risk of atherosclerosis and cardiovascular complications. Thiazolidinediones, more commonly termed glitazones, are the first drugs to specifically target muscular insulin resistance. They have proven efficacy for reducing plasma glucose levels in patients with type 2 diabetes mellitus treated with diet alone, sulphonylureas, metformin or insulin. In addition, they are associated with some improvement of the cardiovascular risk profile. However, troglitazone, the first compound approved by the Food and Drug Administration in the US, proved to be hepatotoxic and was withdrawn from the market after the report of several dozen deaths or cases of severe hepatic failure requiring liver transplantation. It remains unclear whether or not hepatotoxicity is a class effect or is related to unique properties of troglitazone. Rosiglitazone and pioglitazone, two other glitazones, appear to have similar efficacy with regard to blood glucose control in patients with type 2 diabetes mellitus as compared with troglitazone. In controlled clinical trials, the incidence of significant (> or =3 x upper limit of normal) increases in liver enzyme levels (ALT in particular) was similar with rosiglitazone or pioglitazone as compared with placebo, whereas troglitazone was associated with a 3-fold greater incidence. In contrast to the numerous case reports of acute liver failure in patients receiving troglitzone, only a few case reports of hepatotoxicity have been reported in patients treated with rosiglitazone until now, with a causal relationship remaining uncertain. Furthermore, no single case of severe hepatotoxicity has been reported yet with pioglitazone. It should be mentioned that troglitazone, unlike pioglitazone and rosiglitazone, induces the cytochrome P450 isoform 3A4, which is partly responsible for its metabolism, and may be prone to drug interactions. Importantly enough, obesity, insulin resistance and type 2 diabetes mellitus are associated with liver abnormalities, especially non-alcoholic steatohepatitis, independent of any pharmacological treatment. This association obviously complicates the selection of patients who are good candidates for a treatment with glitazones as well as the monitoring of liver tests after initiation of therapy with any thiazolidinedione compound. While regular monitoring of liver enzymes is still recommended and more long term data are desirable, current evidence from clinical trials and postmarketing experience in the US supports the conclusion that rosiglitazone and pioglitazone do not share the hepatotoxic profile of troglitazone.

Aged↗

PubMed2000

Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats.

Thiazolidinedione (TZD) compounds are widely used as oral hypoglycemic agents. Herein, we provide evidence showing that troglitazone, one of the TZD compounds, is able to prevent glomerular dysfunction in diabetic rats through a novel mechanism independent of its insulin-sensitizing action. We examined the effect of troglitazone on functional and biochemical parameters of glomeruli in streptozotocin-induced diabetic rats. Troglitazone was able to prevent not only diabetic glomerular hyperfiltration and albuminuria, but an increase in mRNA expression of extracellular matrix proteins and transforming growth factor-beta1 in glomeruli of diabetic rats, without changing blood glucose levels. Biochemically, an increase in diacylglycerol (DAG) contents and the activation of the protein kinase C (PKC)-extracellular signal-regulated kinase (ERK) pathway in glomeruli of diabetic rats were abrogated by troglitazone. The activation of DAG-PKC-ERK pathways in vitro in mesangial cells cultured under high glucose conditions was also inhibited by troglitazone. Troglitazone enhanced the activities of DAG kinase, which could metabolize DAG to phosphatidic acid, in both glomeruli of diabetic rats and mesangial cells cultured under high glucose conditions. Surprisingly, pioglitazone, another TZD compound without alpha-tocopherol moiety in its structure, also prevented the activation of the DAG-PKC pathway and activated DAG kinase in mesangial cells cultured under high glucose conditions. These results may identify the TZDs as possible new therapeutic agents for diabetic nephropathy that prevent glomerular dysfunction through the inhibition of the DAG-PKC-ERK pathway.

Albuminuria↗

PubMed2003

Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy.

The relationship between insulin action and control of the adipocyte-derived factor adiponectin was studied in age- and weight-matched obese individuals with type 2 diabetes failing sulfonylurea therapy. After initial metabolic characterization, subjects were randomized to troglitazone or metformin treatment groups; all subjects received glyburide (10 mg BID) as well. Treatment was continued for 3 months. The extent of glycemic control after treatment was similar in both groups. However, the increase in maximal insulin-stimulated glucose disposal rate was greater following troglitazone therapy (+44%) compared with metformin treatment (+20%). Troglitazone treatment increased serum adiponectin levels nearly threefold. There was no change in serum adiponectin with metformin treatment. A positive correlation was found between increases in whole-body glucose disposal rates and serum adiponectin levels after troglitazone; no such relationship was seen with metformin. The adiponectin protein content of subcutaneous abdominal adipocytes was increased following troglitazone treatment and unchanged after metformin. Adiponectin release from adipocytes was also augmented with troglitazone treatment. Adiponectin was present in adipocytes and plasma in several multimeric forms; a trimer was the major form secreted from adipocytes. These results indicate that increases in adiponectin content and secretion are associated with improved insulin action but are not directly related to glycemic control. Modulation of adipocyte function, including upregulation of adiponectin synthesis and secretion, may be an important mechanism by which thiazolidinediones influence insulin action.

Adipocytes↗

PubMed1999

Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes.

OBJECTIVE: To examine the effects of a thiazolidinedione (600 mg troglitazone) insulin-sensitizing treatment on total body fat measured by underwater weighing, on intra- and extra-abdominal fat mass using magnetic resonance imaging (MRI), and on anthropometric measures. RESEARCH DESIGN AND METHODS: Type 2 diabetic outpatients were studied in a double-blind randomized trial carried out at Glasgow Royal Infirmary, Scotland. RESULTS: Groups who received troglitazone (8 men, 3 women) and placebo (8 men, 2 women) were well matched for age, BMI, total body fat percentage by underwater weighing, and intra-abdominal fat (kilograms) by MRI. After 12 weeks, body weight changes in the troglitazone group (mean +0.66 kg [95% CI -0.71 to 2.04], P = 0.31) and the placebo group (mean +0.25 kg [-0.64 to 1.13], P = 0.55) were not statistically different. Changes in total body fat with troglitazone (mean +1.02% body wt [-1.13 to 3.17], P = 0.32) and placebo (mean -0.54% body wt [-1.68 to 0.59], P = 0.31) were not significantly different. There was, however, a decrease in intra-abdominal fat mass in the troglitazone-treated group (mean -0.47 kg [-0.79 to -0.13], P = 0.01), and this was significantly different (P = 0.03) from placebo treatment (mean -0.41 kg [-0.77 to -0.05]). CONCLUSIONS: Treatment with the thiazolidinedione troglitazone in human patients with type 2 diabetes decreases intra-abdominal fat mass but does not affect total body fat or weight. This potentially valuable effect points to a differential action on insulin sensitivity in different adipose tissue depots.

Abdomen↗

PubMed2006

A comparison of thiazolidinedione-induced adipogenesis and myogenesis in stromal-vascular cells from subcutaneous adipose tissue or semitendinosus muscle of postnatal pigs.

This study compared the adipogenic potential of porcine stromal-vascular (S-V) cells from semitendinosus muscles and s.c. adipose tissue using thiazolidinediones. Stromal-vascular cells were obtained from s.c. adipose tissue and both semitendinosus muscles from 5- to 7-d-old pigs after collagenase digestion. Preadipocyte recruitment was measured using immunohistological evaluation for AD-3, a preadipocyte antibody. Ciglitazone increased the number of preadipocytes in adipose tissue but not semitendinosus muscle S-V cell cultures, whereas 10 microM troglitazone increased preadipocyte abundance in both adipose and muscle S-V cultures by approximately 3-fold (P < 0.05). Increasing troglitazone doses did not further increase preadipocyte number. Increases in preadipocytes were paralleled by increases in CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) positive cells in adipose tissue S-V cultures, whereas PPARgamma-reactive but not C/EBPalpha-reactive cells were increased in muscle S-V cultures treated with 10 microM troglitazone. Additionally, troglitazone treatment did not increase lipid content in s.c. adipose tissue or muscle S-V cell cultures. Cells plated on laminin-precoated culture dishes were used to determine whether troglitazone influenced adipogenesis or myogenesis in cocultures from muscle S-V cells. There was no effect on the number of myotubes or the average number of nuclei per myotube, suggesting myogenesis was not impaired by troglitazone treatment. These results suggest that regulation of intramuscular adipogenesis differs from that of subcutaneous adipogenesis.

Adipogenesis↗

PubMed2001

[Thiazolidinediones: clinical data and perspectives].

This brief review realizes a synthesis of the main clinical studies of the three thiazolidinediones (TZDs) which have been launched elsewhere, troglitazone, rosiglitazone and pioglitazone. At optimal dose, the three molecules have a similar effect, although slightly weaker for the first, on the fasting plasma glucose and HbA1c levels. They exhibit identical activity, or even higher for troglitazone, in combination with sulfonylureas, metformine and insulin. On the contrary, the three TZDs seem to differentiate according to their effects on lipid metabolism. While rosiglitazone only moderately and inconstantly reduces plasma triglycerides, troglitazone and pioglitazone decreases them by 15 to 25%. LDL-cholesterol levels are almost unaffected by pioglitazone while they increase by 6 to 8% with troglitazone and by more than 10% with rosiglitazone. On the other hand, HDL-cholesterol strongly increases with rosiglitazone and pioglitazone and only slightly on troglitazone. Besides these metabolic effects, TZDs have several properties which could be of therapeutical interest, particularly a possible beta cell protective effect. Except for the severe problems of hepatotoxicity which appear specific to troglitazone and have led to its withdrawal, TZDs are well tolerated. They share as major undesirable effects a risk of peripheral oedema, of anemia due to plasma volume expansion and of weight gain due to the development of subcutaneous adipose tissue. Until now, the European Product licence of rosiglitazone and pioglitazone is limited to the combination with metformin in case of failure of a monotherapy with metformin in obese type 2 diabetic patients and to the combination with a sulphonylurea only in case of intolerance or contra-indication to metformin in type 2 diabetics insufficiently controlled by sulphonylurea therapy at maximal tolerated dose. These indications will probably be enlarged to earlier treatments when long term study results will be available.

Animals↗

PubMed2002

Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells.

Activation of peroxisome proliferator-activated receptor (PPAR)-gamma by the thiazolidinedione (TZD) class of antidiabetic drugs elicits growth inhibition in a variety of malignant tumors. We clarified the effects of TZDs on growth of human non-small cell lung carcinoma (NSCLC) cells that express endogenous PPAR-gamma. Troglitazone and pioglitazone caused inhibition of cellular growth and induced apoptosis of NSCLC cells in a time- and dose-dependent manner. Subtraction cloning analysis identified that troglitazone stimulated expression of the growth arrest and DNA-damage inducible (GADD)153 gene, and the increased expression of GADD153 mRNA was also confirmed by an array analysis of the 160 apoptosis-related genes. Western blot analysis revealed that troglitazone also increased GADD153 protein levels in a time-dependent manner. Troglitazone did not stimulate GADD153 mRNA levels in undifferentiated 3T3-L1 cells lacking PPAR-gamma expression, whereas its induction was clearly observed in differentiated adipocytes expressing PPAR-gamma. Activity of the GADD153 promoter occurred in a NSCLC cell line in transient transcription assays and was significantly stimulated by troglitazone, although binding of PPAR/retinoid X receptor heterodimer was not detected in the promoter region in gel retardation assays. Inhibition of GADD153 gene expression by an antisense phosphorothionate oligonucleotide attenuated the troglitazone-induced growth inhibition. These findings collectively indicated that activation of PPAR-gamma by TZDs could cause growth inhibition and apoptosis of NSCLC cells and that GADD153 might be a candidate factor implicated in these processes.

Apoptosis↗

PubMed2003

PPARgamma ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway.

Ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) induce differentiation and growth inhibition in several human cancers. However, the role of PPARgamma ligands in the growth control of human cholangiocarcinoma cells remains unknown. This study was designed to investigate the biological functions and molecular mechanisms of PPARgamma ligands in the growth regulation of human cholangiocarcinoma cells. Western blot analysis showed that PPARgamma is expressed in all of the three human cholangiocarcinoma cell lines used in this study (SG231, CC-LP-1, and HuCCT1). Transient transfection assays using a peroxisome proliferator response element (PPRE) reporter construct showed that the PPARgamma expressed in human cholangiocarcinoma cells is functional as a transcription activator. Exposure of SG231, CC-LP-1, and HuCCT1 cells to PPARgamma ligands 15-deoxy-delta12, 14-prostaglandin J(2) (15d-PGJ(2)) and troglitazone for 24 to 96 hours resulted in a dose-dependent inhibition of cell growth. Flow cytometry analysis showed that 15d-PGJ(2) and troglitazone-induced cell cycle arrest at the G2/M checkpoint. Consistent with these findings, both 15d-PGJ(2) and troglitazone significantly inhibited the G2/M cyclin-dependent kinase (CDK) Cdc2 activity. Furthermore, cells treated with 15d-PGJ(2) and troglitazone showed elevated expression of p53 and two p53-controlled downstream genes, GADD45 and p21(WAF1/Cip1). Dominant negative inhibition of p53 in SG231 cells significantly blocked the 15d-PGJ(2) and troglitazone-induced growth inhibition, G2/M arrest, and GADD45/p21 induction. 15d-PGJ(2) and troglitazone failed to directly inhibit Cdc2 activity in a cell-free system in spite of direct association between GADD45 and PPARgamma proteins. In conclusion, these results show a novel p53-dependent mechanism in the PPARgamma ligand-mediated inhibition of cholangiocarcinoma growth and suggest a potential therapeutic role of PPARgamma ligands in the treatment of human cholangiocarcinoma.

Bile Duct Neoplasms↗

PubMed2001

Response of experimental retinal neovascularization to thiazolidinediones.

OBJECTIVE: To determine the effect of thiazolidinediones (TZDs) on experimental retinal neovascularization. METHODS: The ability of the TZDs troglitazone and rosiglitazone maleate (1-20 micromol/L) to inhibit retinal endothelial cell (REC) proliferation, migration, tube formation, and signaling was determined in response to vascular endothelial growth factor (VEGF). In vivo studies were performed using the oxygen-induced ischemia model of retinal neovascularization. Neonatal mice were treated with intravitreous injection of 0.5 microL of troglitazone (100 micromol/L) or rosiglitazone maleate (100 micromol/L), or vehicle, and retinal neovascularization was assayed qualitatively and quantitatively by means of angiography and histological examination. RESULTS: Expression of the TZD receptor, peroxisome proliferator-activated receptor gamma, was confirmed in RECs by means of Western immunoblotting. Rosiglitazone and troglitazone inhibited VEGF-induced migration (P< .05), proliferation (P< .05), and tube formation (P< .01) by RECs in vitro beginning at 10 micromol/L. Rosiglitazone and troglitazone inhibited phosphorylation of extracellular signal-regulated mitogen-activated protein kinase 1 in RECs. Intravitreous injection of rosiglitazone or troglitazone inhibited development of retinal neovascularization (P< .01) but did not significantly inhibit VEGF overexpression in the ganglion cell layer of the ischemic retina. CONCLUSION: The TZDs inhibit experimental retinal neovascularization with an effect that is primarily downstream of VEGF expression. CLINICAL RELEVANCE: The TZDs are widely prescribed and should be evaluated for their potential to inhibit the progression of diabetic retinopathy.

Animals↗