噻唑烷抑制乙型肝炎病毒转基因小鼠肝癌

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Hepatology. 2010 Aug;52(2):493-505.

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.

PMID: 20683949


《肝病》 2010年8月，52（2）:493 - 505。

噻唑烷通过过氧化物酶体增殖物激活受体γ- Nucleophosmin的独立监管抑制乙型肝炎病毒转基因小鼠肝癌。

加利甲，切尼英，梅洛吨，波尔瓦尼秒，塔罗基男，Buccoliero男，李斯男，男高音基欧尼L时，奥塔内利乙，福里斯塔五，马斯特罗博尼G号，莫内蒂G号，皮耶拉奇尼G号，苏伦蒂ć，米拉尼南

胃肠病学组，临床病理生理学，佛罗伦萨，意大利部。

抽象
抗糖尿病噻唑（TZD）类有上皮癌的体外抗增殖作用，包括肝细胞肝癌（HCC）。有效的抗癌特性和这些药物在体内的分子机制仍不清楚。另外，主要的TZD类药物，配体依赖的转录因子过氧化物酶体增殖物激活受体γ（PPARgamma），生物的目标是上调，似乎在肝癌肿瘤提供促反应。我们的研究目的是评估TZD类药物是否会影响慢性病管理有关PPARgamma表达和活性体内肝脏癌变。 TZD类药物的口服给药26周的效果测试肿瘤PPARgamma，表达和肝癌PPARgamma缺陷小鼠模型的形成。蛋白质组学分析采用不同的凝胶电泳和质谱分析新鲜分离的肝细胞。 TZD类药物确定的目标，确定培养PPARgamma缺陷肝细胞。 TZD类药物管理乙型肝炎病毒（HBV），（TGN的[Alb1HBV] 44Bri）在肝脏肿瘤的发病率降低，抑制肝细胞增殖和凋亡的增加转基因小鼠。 PPARgamma在乙型肝炎病毒转基因小鼠（Tg的[乙肝] CreKOgamma肝删除）并没有改变，但增加了肝脏癌变TZD类药物的抑瘤效果。蛋白质组分析，在PPARgamma缺陷肝二酮Nucleophosmin的目标确定（故宫）。 TZD类药物会抑制蛋白质和信使RNA的表达水平，降低故宫故宫启动子活性。 TZD类药物相关的故宫抑制磷酸化与p53和p21表达的诱导。结论：这些结果表明，TZD类药物治疗慢性政府已经通过了故宫表达抑制肝脏中的抗癌活性，并表明这些药物可能对肝癌的化学预防和治疗作用。肝病2010年。

PMID：20683949



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Thiazolidinediones inhibit HCC in hbv
by stefano170669 , Aug 09, 2010 09:06PM
http://archive.mail-list.com/hbv ... 54.cbb98033.en.html

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.

http://en.wikipedia.org/wiki/Thiazolidinedione

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?

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Thiazolidinedione
From Wikipedia, the free encyclopedia
Jump to: navigation, search
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)

Insulin Sensitizers Biguanides Metformin# · Buformin‡ · Phenformin‡

TZDs (PPAR) Pioglitazone · Rivoglitazone† · Rosiglitazone · Troglitazone‡

Dual PPAR agonists Aleglitazar† · Muraglitazar§ · Tesaglitazar§


Secretagogues K+ ATP Sulfonylureas 1st generation: Acetohexamide · Carbutamide · Chlorpropamide · Gliclazide · Tolbutamide · Tolazamide

2nd generation: Glibenclamide (Glyburide)# · Glipizide · Gliquidone · Glyclopyramide

3rd generation: Glimepiride

Meglitinides/"glinides" Nateglinide · Repaglinide · Mitiglinide


GLP-1 analogs Exenatide · Liraglutide · Taspoglutide† · Albiglutide†

DPP-4 inhibitors Alogliptin† · Linagliptin† · Saxagliptin · Sitagliptin · Vildagliptin


Analogs/other insulins fast acting (Insulin lispro · Insulin aspart · Insulin glulisine) · Short acting (Regular insulin) · long acting (Insulin glargine · Insulin detemir) · Inhalable insulin (Exubera)‡ · NPH insulin


Other Alpha-glucosidase inhibitors Acarbose · Miglitol · Voglibose

Amylin analog Pramlintide

SGLT2 inhibitors Canagliflozin† · Dapagliflozin† · Remogliflozin† · Sergliflozin†

Other Benfluorex · Tolrestat‡


#WHO-EM. ‡Withdrawn from market. CLINICAL TRIALS: †Phase III. §Never to phase III

M: END
anat/phys/devp/horm/cell
noco(d)/cong/tumr, sysi/epon
proc, drug (A10/H1/H3/H5)





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