Disease relevance of rosiglitazone

• Dose-response clonogenic assays of the PC-3 prostate cancer cell line with troglitazone showed an antiproliferative effect (ED50, 3 x 10(-7) M) and other PPARgamma ligands (BRL49653: ED50, 8 x 10(-8) M; 15-deoxy-delta12,14-prostaglandin J2: ED50, 2 x 10(-6) M; ciglitizone: ED50, not reached; indomethacin: ED50, not reached) showed similar effects [1].
• Enhanced marrow adipogenesis and bone resorption in estrogen-deprived rats treated with the PPARgamma agonist BRL49653 (rosiglitazone) [2].
• We found that human non-small cell lung carcinoma cell lines (H1838 and H2106) express EP2 receptors, and that the inhibition of cell growth by PPARgamma ligands (GW1929, PGJ2, ciglitazone, troglitazone, and rosiglitazone [also known as BRL49653]) was associated with a significant decrease in EP2 mRNA and protein levels [3].
• Effect of the thiazolidinedione BRL49653 and genetic obesity on hepatic gene expression in the Zucker rat [4].
• JTP-426467 antagonized PPARgamma agonistic action by BRL49653 in KK-Ay mice on high-fat diet, in terms of plasma glucose, body weight gain and interscapular brown adipose tissue (IBAT) weight [5].

High impact information on rosiglitazone

• We also describe the ternary complex containing the PPAR-gamma LBD, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 A resolution [6].
• Consistent with a participation of the PPARgamma signaling pathway, BRL49653 reduced CCR2 expression in freshly isolated human monocytes ex vivo and in circulating mouse monocytes in vivo [7].
• The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro [8].
• In contrast, Ro inhibited induction of broad subsets of lipopolysaccharide and IFN-gamma target genes in a gene-specific and PPARgamma-dependent manner [9].
• The ED50 for inhibition of leptin expression by the thiazolidinedione BRL49653 was between 5 and 50 nM, similar to its Kd for binding to PPARgamma [10].

Biological context of rosiglitazone

• PPAR gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure [11].
• Here we report that the ectopic expression of RGS2 using a retroviral system in mouse NIH-3T3 cells promotes adipogenesis only in the presence of BRL49653, which is a ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma) [12].
• Treatment of cultured-activated HSC with ligands for PPARgamma (10 microm 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)); 0.1 approximately 10 microm BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability [13].
• [(3)H]azPC bound recombinant PPARgamma with an affinity (K(d)((app)) approximately 40 nm) that was equivalent to rosiglitazone (BRL49653), and competition with rosiglitazone showed that binding occurred in the ligand-binding pocket. azPC induced PPRE reporter gene expression, as did rosiglitazone, with a half-maximal effect at 100 nm [14].
• Moreover, when used at submaximally effective concentrations, BRL49653 and 2-bromopalmitate act in an additive manner to induce gene expression in preadipose cells, but this additivity of effects is lost when one of the compounds is used at a maximally effective concentration [15].

Anatomical context of rosiglitazone

• The intronic PPAR-response element (PPRE) mediates induction by endogenous PPARgamma in murine adipocytes and confers responsiveness to the PPARgamma-selective ligand BRL49653 [16].
• Treatment of M2-10B4 as well as 3T3-L1 preadipocytes with MM-LDL, but not native LDL, promoted adipogenic differentiation in the presence of peroxisome proliferator-activated receptor (PPAR) gamma agonist thiazolidinediones, BRL49653 and ciglitizone [17].
• While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression [18].
• Using mRNA differential display, we have compared 3T3-L1 cells treated to differentiate in the presence of BRL49653 with untreated 3T3-L1 cells and identified Fos-related antigen 1 (Fra-1), a member of the Fos protein family, as a novel molecular target for BRL49653 action in 3T3-L1 cells [19].
• We measured effects of the thiazolidinedione BRL49653 on bone tissue of intact and estrogen-deprived skeletally mature adult female Wistar rats (6-9 months old) [2].

Associations of rosiglitazone with other chemical compounds

• The relatively weak, nonthiazolidinedione PPAR activator WY 14,643 also inhibited leptin expression, but was approximately 1000 times less potent than BRL49653 [10].
• PPARalpha bound specifically to immobilized palmitoyl-CoA and Wy14643, but not BRL49653, abolished binding [20].
• Like troglitazone, two other thiazolidinediones, ciglitazone and englitazone, exhibited similar inhibitory effect on cholesterol synthesis; however, other known PPAR-gamma ligands such as BRL49653, pioglitazone, and 15-deoxy-delta(12,14)-prostaglandin J2 showed only weak or no inhibition [21].
• RESULTS: In animals treated with LG100268 or BRL49653, serum glucose, glycohaemoglobin and the cardiovascular risk factor, fibrinogen, decreased to the same extent [22].
• Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone [18].

Gene context of rosiglitazone

• BRL49653 treatment of subcutaneously, but not omentally, derived preadipocytes stimulated expression of UCP2 mRNA (5.1+/-1.1 fold) [23].
• The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM [24].
• Incubation with TNF-alpha and BRL49653 caused an additional twofold increase in COX-2 expression [25].
• Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte [18].
• Analysis of all members of the Fos-Jun family of transcription factors showed that Fra-1 was the only member that was specifically up-regulated by BRL49653 [19].

Analytical, diagnostic and therapeutic context of rosiglitazone

• Apo C-II mRNA levels were not affected after treatment with BRL49653, a peroxisome proliferator-activated receptor (PPAR)gamma-specific ligand, suggesting that fibrates act on apo C-II expression via PPARalpha [26].
• In cell culture experiments, the PPARgamma-selective ligand BRL49653 moderately inhibited growth of BT4Cn cells, whereas administration of TTA resulted in a marked growth inhibition [27].
• MEASUREMENTS: A competitive reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantify UCP2 mRNA expression in human omental and subcutaneous adipocytes, and in cultured human preadipocytes differentiated in vitro using the thiazolidinedione, BRL49653 [23].

References