Safety issues and prospects for future generations of PPAR modulators

Rubenstrunk, Anne; Hanf, R.; Hum, Dean W.; Fruchart, Jean‐Charles; Staels, Bart

doi:10.1016/j.bbalip.2007.02.003

Cited by 278 publications

(240 citation statements)

References 192 publications

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“…Unfortunately, these synthetic TZDs cause undesired side-and offtarget effects (higher rate of bone fractures, weight gain, edema, renal function failure, etc.) [25][26][27]. More recently, identification and characterization of specific PPARc ligands known as SPPARMs (Selective PPARc Modulators), displaying beneficial antidiabetic action with no or reduced side-effects, are gaining interest [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Zurlo

Ziccardi

Votino

et al. 2016

Biochemical Pharmacology

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a b s t r a c tCladosporols are secondary metabolites from Cladosporium tenuissimum characterized for their ability to control cell proliferation. We previously showed that cladosporol A inhibits proliferation of human colon cancer cells through a PPARc-mediated modulation of gene expression. In this work, we investigated cladosporol B, an oxidate form of cladosporol A, and demonstrate that it is more efficient in inhibiting HT-29 cell proliferation due to a robust G0/G1-phase arrest and p21 waf1/cip1 overexpression. Cladosporol B acts as a PPARc partial agonist with lower affinity and reduced transactivation potential in transient transfections as compared to the full agonists cladosporol A and rosiglitazone. Site-specific PPARc mutants and surface plasmon resonance (SPR) experiments confirm these conclusions. Cladosporol B in addition displays a sustained proapoptotic activity also validated by p21 waf1/cip1 expression analysis in the presence of the selective PPARc inhibitor GW9662. In the DMSO/H 2 O system, cladosporols A and B are unstable and convert to the ring-opened compounds 2A and 2B. Finally, docking experiments provide the structural basis for full and partial PPARc agonism of 2A and 2B, respectively. In summary, we report here, for the first time, the structural characteristics of the binding of cladosporols, two natural molecules, to PPARc. The binding of compound 2B is endowed with a lower transactivation potential, higher antiproliferative and proapoptotic activity than the two full agonists as compound 2A and rosiglitazone (RGZ).

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Section: Introductionmentioning

confidence: 99%

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Zurlo

Ziccardi

Votino

et al. 2016

Biochemical Pharmacology

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“…PPAR-γ agonists have been shown to induce apoptosis in several malignant cell lines (Elstner et al, 1998) and to inhibit the invasive activity of colon and breast cancer cells (Liu et al, 2003). In contrast, animal toxicity studies have suggested a possible increased cancer risk in multiple organs in association with a wide variety of PPAR-γ and dual PPARα/γ agonists (Rubenstrunk et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Use of Oral Antidiabetic Drugs (Metformin and Pioglitazone) in Diabetic Patients with Breast Cancer: How Does It Effect on Serum Hif-1 Alpha and 8Ohdg Levels?

Harman¹,

Erten²,

Küçükzeybek³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Objective: The aim was to investigate indicators related to DNA damage and cancer pathogenesis in Type II diabetes cases with breast cancer. It was planned to evaluate the relationship between these markers with oral antidiabetic drugs. Research Design and Methods: Fourty patients and 10 healthy individuals were included in the study. HIF-1α and 8-OHdG are examined in blood samples taken from these individuals with an ELISA Kit. Statistical analysis of data was performed with 95% confidence using Windows package program SPSS 15.0. Results: HIF-1α parameters were found to be meaningfully higher in the patient group than the controls in both pretreatment and posttreatment periods (p<0.05). No significant differences in terms of 8-OHdG between patients and controls. However, posttreatment serum HIF-1α ve 8-OHdG levels was found lower than pretreatment levels in patients receiving metformin, but not with pioglitazone. Conversely, serum 8-OHdG levels decreased significantly in these patients. When patients were evaluated according to the treatment groups (pioglitazone vs. metfformin) no significant differences in terms of serum HIF-1α and 8-OHdG levels between treatment groups. Conclusions: HIF-1α levels decreased significantly in the patient group receiving metformin. However, there was no significant difference in terms of HIF-1α levels in the patients receiving pioglitazone.

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“…120,121 Several early-phase clinical studies have been performed to evaluate the efficacies of TZDs in various types of cancers. Recently, a phase II clinical trial of rosiglitazone was conducted in 12 patients with liposarcoma to evaluate clinical response.…”

Section: Safety Issues and Pparγ Agonists In Clinical Developmentmentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ in bladder cancer: A promising therapeutic target

Mansure¹,

Nassim²,

Kassouf³

2009

Cancer Biology & Therapy

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Safety issues and prospects for future generations of PPAR modulators

Cited by 278 publications

References 192 publications

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

Use of Oral Antidiabetic Drugs (Metformin and Pioglitazone) in Diabetic Patients with Breast Cancer: How Does It Effect on Serum Hif-1 Alpha and 8Ohdg Levels?

Peroxisome proliferator-activated receptor γ in bladder cancer: A promising therapeutic target

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