生物活性

• 描述Troglitazone is a selective thiazolidinedione-based PPARγ agonist with EC50 values of 780nM and 550nM for PPAR-GAL4 transactivation assay of murine receptor and human receptor, respectively, with no obvious effect on PPARα and PPARδ up to 10μM^[1]. Troglitazone is used as an antidiabetic agent. It has hypoglycemic effects in insulin-resistant animal models and non-insulin-dependent diabetic humans. Also its effect on acute increase in vivo insulin action in normal rats has also been found^[2]. Troglitazone led a time-(50μM, 1-7days) and dose (50-100μM, in 3 days)-dependent antiproliferative effect on HL-60 cells, with effect on cell arrest at the G1 phase and differentiation into monocytes by Troglitazone found^[3]. Similar antiproliferation and redifferentiation effect on thyroid cancer cell lines has also been found. Troglitazone-induced downregulation of surface expression of CD97, a novel dedifferentiation marker, in FTC-133 cells, and upregulation of sodium iodide symporter (NIS) mRNA in both TPC-1 and FTC-133 cells could be observed^[4]. Troglitazone dose‑dependently inhibited cell migration and invasion of PC‑3 cells within 6-24h at concentration of 1, 10 and 40μM and increased the mRNA and protein levels of E‑cadherin and glutathione peroxidase 3 (GPx3) at concentration of 10μM after 24h^[5].
• 作用机制Troglitazone thiazolidinedione-based PPARγ agonist which may directly bind to the AF-2 helix and stabilize the formation of the charge clamp on the surface of PPAR critical for recruitment of coactivator proteins to the receptor complex through their LxxLL motifs.^[1]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  3T3L1 cells	-	Function assay	-	Increase in 2-deoxyglucose uptake in mouse 3T3L1 cells at 3 uM by liquid scintillation counter	18477507
  3T3L1 cells	-	Function assay	-	Agonist activity at PPARgamma in mouse 3T3L1 cells, EC50=1 μM	21493073
  3T3-L1 cells	-	Function assay	-	Effective concentration for 50% enhancement of insulin-induced triglyceride accumulation in 3T3-L1 cells, EC50=0.13 μM	9599241

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• 动物研究
  剂量	Rat: 0.05 mg/kg - 0.1 mg/kg[6] (p.o., BID); 25 mg/kg - 200 mg/kg[7] (female rats, p.o.) Mice: 10 mg/kg - 30 mg/kg[8] (i.p.); 50 mg/kg - 800 mg/kg[7] (p.o.) Pig: 10 mg/kg[9] (i.v.) Cynomolgus monkeys: 300 mg/kg - 1200 mg/kg[10] (p.o.)
  给药途径	p.o., i.p., i.v.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02456428	-	-	Completed	-	Canada, Quebec ... more >> Lady Davis Institute for Medical Research, Jewish General Hospital Montreal, Quebec, Canada, H3T1E2 Collapse <<
  NCT03492580	-	-	Completed	-	United States, New Jersey ... more >> Janssen Investigative Site Titusville, New Jersey, United States, 08560 Collapse <<
  NCT02476760	-	-	Completed	-	Canada, Quebec ... more >> Lady Davis Institute for Medical Research, Jewish General Hospital Montreal, Quebec, Canada, H3T1E2 Collapse <<

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• 参考文献

• [1] Willson TM, Brown PJ, et al. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000 Feb 24;43(4):527-50.

  [2] Lee MK, Olefsky JM, et al. Acute effects of troglitazone on in vivo insulin action in normal rats. Metabolism. 1995 Sep;44(9):1166-9.

  [3] Fujimura S, Suzumiya J, et al. Effects of troglitazone on the growth and differentiation of hematopoietic cell lines. Int J Oncol. 1998 Dec;13(6):1263-7.

  [4] Park JW, Zarnegar R, et al. Troglitazone, the peroxisome proliferator-activated receptor-gamma agonist, induces antiproliferation and redifferentiation in human thyroid cancer cell lines. Thyroid. 2005 Mar;15(3):222-31.

  [5] Chang SN, Lee JM, et al. Troglitazone inhibits the migration and invasion of PC-3 human prostate cancer cells by upregulating E-cadherin and glutathione peroxidase 3. Oncol Lett. 2018 Oct;16(4):5482-5488.

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