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Pleiotropic effects of glitazones: a double edge sword?

Salomone S - Front Pharmacol (2011)

Bottom Line: Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential.The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects.Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Biomedicine, Catania University Catania, Italy.

ABSTRACT
Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

No MeSH data available.


Related in: MedlinePlus

Scheme of PPARγ activation and signaling. (A) In the absence of ligand, PPARγ is bound to co-repressors and may interact with DNA in a manner that prevent transcription. (B) Upon binding the ligand, PPARγ undergoes conformational changes inducing the recruitment of specific co-activators and allowing hetero-dimerization with retinoid receptors. These multimeric complex activates transcriptional activity and gene expression. L, ligand; RXR, retinoid receptor; LBD, ligand binding domain; DBD, DNA binding domain; PPRE, PPAR responsive element; SRC-1, steroid receptor co-activator-1; HAT, histone acetyl transferase.
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Figure 2: Scheme of PPARγ activation and signaling. (A) In the absence of ligand, PPARγ is bound to co-repressors and may interact with DNA in a manner that prevent transcription. (B) Upon binding the ligand, PPARγ undergoes conformational changes inducing the recruitment of specific co-activators and allowing hetero-dimerization with retinoid receptors. These multimeric complex activates transcriptional activity and gene expression. L, ligand; RXR, retinoid receptor; LBD, ligand binding domain; DBD, DNA binding domain; PPRE, PPAR responsive element; SRC-1, steroid receptor co-activator-1; HAT, histone acetyl transferase.

Mentions: Glitazones (also referred to as thiazolidinediones) are drugs approved for use in the treatment of diabetes mellitus type 2; they include ciglitazone, pioglitazone, troglitazone, rosiglitazone, rivoglitazone, and balaglitazone. Despite their striking chemical similarity (Figure 1A), these compounds have different safety profiles, such that only pioglitazone is currently still in clinical use; ciglitazone never reached the market, troglitazone and more recently rosiglitazone have been withdrawn (rosiglitazone is still sold in United States, but put under restriction), while rivoglitazone and balaglitazone are still in development. After being introduced in the 1990s, glitazones became very popular and widely prescribed, because they increase insulin sensitivity without causing hypoglycemia, until some clinical studies raised concerns on their safety (see below). In 2009 pioglitazone was selling for about 2.5 billion $ in United States, ranking ninth among top selling drugs (Drugs.com1). Glitazones act by binding to peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor involved in regulation of insulin sensitivity and glucose metabolism (Francis et al., 2003). Following activation by exogenous ligands, such as glitazones, or endogenous ligands, such as free fatty acids and eicosanoids, PPARγ modulates transcription of genes involved in carbohydrate and lipid metabolism (Figure 2; Francis et al., 2003). PPARγ-dependent effects of glitazones include decrease of insulin resistance (Fujita et al., 1983), induction of adipocyte differentiation (Kletzien et al., 1992), inhibition of vascular endothelial growth factor (VEGF)-induced angiogenesis (Panigrahy et al., 2002), change in levels of leptin (De Vos et al., 1996) and adiponectin (Yamauchi et al., 2001), decrease in levels of some cytokines (Jiang et al., 1998; Ricote et al., 1998), including tumor necrosis factor α (TNFα), and interleukin-6 (IL-6; Sigrist et al., 2000), though this latter effect may also be, in part, PPARγ-independent (see below). Glitazones also upregulate the expression of genes involved in fatty acid uptake, beta-oxidation, electron transport, and oxidative phosphorylation in subcutaneous fat (Boden et al., 2005), which may reduce plasma levels of lipids. Glitazones induce a moderate decrease in triglycerides and free fatty acids and an increase in high-density lipoprotein (HDL) cholesterol, while increasing the size/decreasing the density of low-density lipoprotein (LDL; Goldberg, 2006). This list of effects induced by glitazones is far from being complete, but may give an idea of the multiplicity of genes regulated following PPARγ stimulation; these genes go beyond glucose and lipid metabolism, encompassing inflammation (cytokines), cell growth and differentiation, angiogenesis (VEGF), which provides the basis for additional potential therapeutic indications. In fact, beside diabetes, glitazones have been investigated in a number of diseases, such as non-alcoholic steatohepatitis (Neuschwander-Tetri et al., 2003), psoriasis (Ellis et al., 2000), autism (Boris et al., 2007), polycystic ovary syndrome (Katsiki et al., 2009), and other conditions, potentially including also breast carcinoma (Baranova, 2008).


Pleiotropic effects of glitazones: a double edge sword?

Salomone S - Front Pharmacol (2011)

Scheme of PPARγ activation and signaling. (A) In the absence of ligand, PPARγ is bound to co-repressors and may interact with DNA in a manner that prevent transcription. (B) Upon binding the ligand, PPARγ undergoes conformational changes inducing the recruitment of specific co-activators and allowing hetero-dimerization with retinoid receptors. These multimeric complex activates transcriptional activity and gene expression. L, ligand; RXR, retinoid receptor; LBD, ligand binding domain; DBD, DNA binding domain; PPRE, PPAR responsive element; SRC-1, steroid receptor co-activator-1; HAT, histone acetyl transferase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108480&req=5

Figure 2: Scheme of PPARγ activation and signaling. (A) In the absence of ligand, PPARγ is bound to co-repressors and may interact with DNA in a manner that prevent transcription. (B) Upon binding the ligand, PPARγ undergoes conformational changes inducing the recruitment of specific co-activators and allowing hetero-dimerization with retinoid receptors. These multimeric complex activates transcriptional activity and gene expression. L, ligand; RXR, retinoid receptor; LBD, ligand binding domain; DBD, DNA binding domain; PPRE, PPAR responsive element; SRC-1, steroid receptor co-activator-1; HAT, histone acetyl transferase.
Mentions: Glitazones (also referred to as thiazolidinediones) are drugs approved for use in the treatment of diabetes mellitus type 2; they include ciglitazone, pioglitazone, troglitazone, rosiglitazone, rivoglitazone, and balaglitazone. Despite their striking chemical similarity (Figure 1A), these compounds have different safety profiles, such that only pioglitazone is currently still in clinical use; ciglitazone never reached the market, troglitazone and more recently rosiglitazone have been withdrawn (rosiglitazone is still sold in United States, but put under restriction), while rivoglitazone and balaglitazone are still in development. After being introduced in the 1990s, glitazones became very popular and widely prescribed, because they increase insulin sensitivity without causing hypoglycemia, until some clinical studies raised concerns on their safety (see below). In 2009 pioglitazone was selling for about 2.5 billion $ in United States, ranking ninth among top selling drugs (Drugs.com1). Glitazones act by binding to peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor involved in regulation of insulin sensitivity and glucose metabolism (Francis et al., 2003). Following activation by exogenous ligands, such as glitazones, or endogenous ligands, such as free fatty acids and eicosanoids, PPARγ modulates transcription of genes involved in carbohydrate and lipid metabolism (Figure 2; Francis et al., 2003). PPARγ-dependent effects of glitazones include decrease of insulin resistance (Fujita et al., 1983), induction of adipocyte differentiation (Kletzien et al., 1992), inhibition of vascular endothelial growth factor (VEGF)-induced angiogenesis (Panigrahy et al., 2002), change in levels of leptin (De Vos et al., 1996) and adiponectin (Yamauchi et al., 2001), decrease in levels of some cytokines (Jiang et al., 1998; Ricote et al., 1998), including tumor necrosis factor α (TNFα), and interleukin-6 (IL-6; Sigrist et al., 2000), though this latter effect may also be, in part, PPARγ-independent (see below). Glitazones also upregulate the expression of genes involved in fatty acid uptake, beta-oxidation, electron transport, and oxidative phosphorylation in subcutaneous fat (Boden et al., 2005), which may reduce plasma levels of lipids. Glitazones induce a moderate decrease in triglycerides and free fatty acids and an increase in high-density lipoprotein (HDL) cholesterol, while increasing the size/decreasing the density of low-density lipoprotein (LDL; Goldberg, 2006). This list of effects induced by glitazones is far from being complete, but may give an idea of the multiplicity of genes regulated following PPARγ stimulation; these genes go beyond glucose and lipid metabolism, encompassing inflammation (cytokines), cell growth and differentiation, angiogenesis (VEGF), which provides the basis for additional potential therapeutic indications. In fact, beside diabetes, glitazones have been investigated in a number of diseases, such as non-alcoholic steatohepatitis (Neuschwander-Tetri et al., 2003), psoriasis (Ellis et al., 2000), autism (Boris et al., 2007), polycystic ovary syndrome (Katsiki et al., 2009), and other conditions, potentially including also breast carcinoma (Baranova, 2008).

Bottom Line: Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential.The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects.Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Biomedicine, Catania University Catania, Italy.

ABSTRACT
Glitazones (thiazolidinediones) are drugs used for diabetes mellitus type 2. By binding to peroxisome proliferator-activated receptor γ (PPARγ) they modulate transcription of genes of carbohydrate and lipid metabolism. Through PPARγ stimulation, however, glitazones also affect other genes, encompassing inflammation, cell growth and differentiation, angiogenesis, which broads their therapeutic potential. The gene expression profile induced by each glitazone shows peculiarities, which may affect its benefit/risk balance; indeed, troglitazone and rosiglitazone have been associated with liver failure and coronary disease, respectively; whether or not these severe adverse effects are solely related to PPARγ remains yet unclear, since glitazones exert also PPARγ-independent effects. Glitazone chemistry serves as scaffold for synthesizing new compounds with PPARγ-independent pharmacological properties and we report here a preliminary observation of inhibition of vasoconstriction by troglitazone in isolated vessels, an effect that appears fast, reversible, and PPARγ-independent. Pleiotropic effects of glitazones need specific attention in terms of drug safety, but also provide basis for drug development and novel experimental therapeutics.

No MeSH data available.


Related in: MedlinePlus