Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin.
Galli A, Ceni E, Mello T, Polvani S, Tarocchi M, Buccoliero F, Lisi F, Cioni L, Ottanelli B, Foresta V, Mastrobuoni G, Moneti G, Pieraccini G, Surrenti C, Milani S.
Gastroenterology Unit, Department of Clinical Pathophysiology, Florence, Italy.
Abstract
Antidiabetic thiazolidinediones (TZD) have in vitro antiproliferative effect in epithelial cancers, including hepatocellular carcinoma (HCC). The effective anticancer properties and the underlying molecular mechanisms of these drugs in vivo remain unclear. In addition, the primary biological target of TZD, the ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), is up-regulated in HCC and seems to provide tumor-promoting responses. The aim of our study was to evaluate whether chronic administration of TZD may affect hepatic carcinogenesis in vivo in relation to PPARgamma expression and activity. The effect of TZD oral administration for 26 weeks was tested on tumor formation in PPARgamma-expressing and PPARgamma-deficient mouse models of hepatic carcinogenesis. Proteomic analysis was performed in freshly isolated hepatocytes by differential in gel electrophoresis and mass spectrometry analysis. Identified TZD targets were confirmed in cultured PPARgamma-deficient hepatocytes. TZD administration in hepatitis B virus (HBV)-transgenic mice (TgN[Alb1HBV]44Bri) reduced tumor incidence in the liver, inhibiting hepatocyte proliferation and increasing apoptosis. PPARgamma deletion in hepatocytes of HBV-transgenic mice (Tg[HBV]CreKOgamma) did not modify hepatic carcinogenesis but increased the TZD antitumorigenic effect. Proteomic analysis identified nucleophosmin (NPM) as a TZD target in PPARgamma-deficient hepatocytes. TZD inhibited NPM expression at protein and messenger RNA levels and decreased NPM promoter activity. TZD inhibition of NPM was associated with the induction of p53 phosphorylation and p21 expression. Conclusion: These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment. HEPATOLOGY 2010.
Conclusion: These findings suggest that chronic administration of TZD has anticancer activity in the liver via inhibition of NPM expression and indicate that these drugs might be useful for HCC chemoprevention and treatment. HEPATOLOGY 2010.
this drug is same family as Rosiglitazone (Avandia) which has been foud active on hbsag and hbvdna, question is does TZD lower hbsag since decrease of hbsag inibits cancer growth too and if lowered to und eradicate hbv?作者: zasxz 时间: 2010-8-11 12:23 标题: Thiazolidinedione From Wikipedia, the free encyclopedia
Thiazolidinedione
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The thiazolidinediones (pronounced /θaɪəˌzoʊlɨdiːnˈdaɪoʊn/), also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.
Contents [hide]
1 Mode of action
2 Members of the class
3 Uses
4 Side effects and contraindications
5 Footnotes
[edit] Mode of action
Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPARγ (gamma). The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.
Genes upregulated by PPARγ can be found in the main article on peroxisome proliferator-activated receptors.
By activating PPARγ:
Insulin resistance is decreased
Adipocyte differentiation is modified [1]
VEGF-induced angiogenesis is inhibited[2]
Leptin levels decrease (leading to an increased appetite)
Levels of certain interleukins (e.g. IL-6) fall
Adiponectin levels rise
TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unkown. Circulating levels of free fatty acids are also reduced by TZDs.
[edit] Members of the class
The chemical structure of thiazolidinedioneChemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
Rosiglitazone (Avandia)
Pioglitazone (Actos)
Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.
Experimental agents include MCC-555, a powerful antidiabetic agent, rivoglitazone, and the early non-marketed thiazolidinedione ciglitazone.
Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a rhodanine.
[edit] Uses
The only approved use of the thiazolidinediones is in diabetes mellitus type 2.
It is being investigated experimentally in polycystic ovary syndrome (PCOS), non-alcoholic steatohepatitis (NASH),[3] psoriasis,[4] autism,[5] ovarian hyperstimulation syndrome (by VEGF inhibition in granulosa cells)[6] and other conditions.[7]
Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of the protection against initial stages of the breast carcinoma development.
[edit] Side effects and contraindications
The withdrawal of troglitazone has led to concerns of the other thiazolidinediones also increasing the incidence of hepatitis and potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, rosiglitazone and pioglitazone have been free of this problem.
The main side effect of all thiazolidinediones is water retention, leading to edema, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (NYHA grade III or IV heart failure).
Though recent studies have shown there may be an increased risk of coronary heart disease and heart attacks with rosiglitazone[8] pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progression[9][10][11].
[edit] Footnotes
^ Waki H, Yamauchi T, Kadowaki T (February 2010). "[Regulation of differentiation and hypertrophy of adipocytes and adipokine network by PPARgamma]" (in Japanese). Nippon Rinsho 68 (2): 210–6. PMID 20158086.
^ Panigrahy D, Singer S, Shen LQ, et al. (2002). "PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis". J. Clin. Invest. 110 (7): 923–32. doi:10.1172/JCI15634. PMID 12370270.
^ Belfort R, Harrison SA, Brown K, et al. (November 2006). "A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis". N. Engl. J. Med. 355 (22): 2297–307. doi:10.1056/NEJMoa060326. PMID 17135584. Clinical trial info
^ Krentz AJ, Friedmann PS (March 2006). "Type 2 diabetes, psoriasis and thiazolidinediones". Int. J. Clin. Pract. 60 (3): 362–3. doi:10.1111/j.1368-5031.2005.00765.x. PMID 16494655.
^ Boris et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children, Journal of Neuroinflammation 2007,4:3 [1]
^ Shah DK, Menon KM, Cabrera LM, Vahratian A, Kavoussi SK, Lebovic DI (April 2010). "Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro". Fertil. Steril. 93 (6): 2042–7. doi:10.1016/j.fertnstert.2009.02.059. PMID 19342033.
^ Clinical Trials for Rosiglitazone - from ClinicalTrials.gov, a service of the U.S. National Institutes of Health
^ "Avandia to Carry Stronger Heart Failure Warning - Forbes.com". http://www.forbes.com/forbeslife ... /hscout607350.html. Retrieved 2007-08-15.
^ Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A (July 2004). "The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients". Diabetes Care 27 (7): 1647–53. doi:10.2337/diacare.27.7.1647. PMID 15220241. http://care.diabetesjournals.org/cgi/content/abstract/27/7/1647.
^ Mannucci E, Monami M, Lamanna C, Gensini GF, Marchionni N (May 2008). "Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials". Diabetes Obes Metab 0 (12): 080526191604039. doi:10.1111/j.1463-1326.2008.00892.x. PMID 18505403.
^ Nissen SE, Nicholls SJ, Wolski K, et al. (April 2008). "Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial". JAMA 299 (13): 1561–73. doi:10.1001/jama.299.13.1561. PMID 18378631. http://jama.ama-assn.org/cgi/content/full/299/13/1561.
[hide]v • d • eOral anti-diabetic drugs and Insulin analogs (A10)