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Rat carcinogenicity study with GW501516, a PPAR delta agonist
... It stated that this substance, once a developmental drug, was withdrawn from research and terminated when serious toxicities were discovered in animal subjects (40). The long-term carcinogenicity studies (104-week long) at high doses showed that administration of GW501516 to rats (40 mg/kg/day) and mice (80 mg/kg/day) leads to neoplastic findings in multiple tissues (41,42). Mortality of female Han Wistar rats was increased at all doses mostly due to development of uterine endometrial adenocarcinoma. ...
... Mortality of female Han Wistar rats was increased at all doses mostly due to development of uterine endometrial adenocarcinoma. Other types of identified neoplasms affected such organs as stomach, liver, and urinary bladder, and their prevalence seemed to be a confluence of such factors as dose and gender (41). Survival of CD1 mice also significantly decreased at doses ≥30 mg/kg/d and led to combined squamous cell tumours (at all doses) and neoplastic changes in liver and stomach (42). ...
In 2008, the team of Ronald Evans, a professor at the Salk Institute Gene Expression Laboratory, published an article about the effects of two metabolic modulators branded as GW501516 and AICAR on physical endurance of laboratory animals. Both substances, also called 'exercise pills' or 'exercise mimetics', showed the ability to cause multidirectional changes in muscle metabolism. In particular, they stimulated fatty acid oxidation and promoted muscle remodelling. These compounds were regarded as very promising drug candidates for the treatment of diseases such as obesity and type 2 diabetes. GW501516 and AICAR have received considerable attention in doping control due to assumed performance-enhancing properties and recent confiscations of illicitly distributed drugs containing AICAR. Therefore, the World Anti-Doping Agency added GW501516 and AICAR to the Prohibited List in 2009. This review covers the cellular and systemic effects of the metabolic modulators' administration with special emphasis on their role in exercise metabolism. It also presents the advancements in development of methodologies for the detection of their abuse by athletes.
... The peroxisome proliferator activated receptor β/δ (PPARβ/δ) agonist GW501516 completed proof-of-concept clinical trials successfully for dyslipidaemia (Ooi et al., 2011) and hypercholesteremia (Olson et al., 2012), however this drug has been precluded from further clinical trials by GlaxoSmithKline (GSK) due to preclinical data showing a link with tumour development (Geiger et al., 2009; Olson et al., 2012; Newsholme et al., 2009). However, scientists haven't given up on GW501516 and GW0742, and a large volume of papers have been published on the therapeutic potential use of these drugs, despite the announcement from GSK to discontinue clinical trials. ...
... There are several conflicting studies showing the direct effects of oral dosing rats and mice of GW501516 leading to either the induction or inhibition of carcinoma (Table 3 ). Looking closely at the experimental design it seems that there is a direct correlation between dose and outcome, with doses of GW501516 10 mg/kg/day for 6 weeks inducing detrimental side effects such as rectal bleeding in mice (Gupta et al., 2004 ) and at 10 to 100 mg/kg/day for 104 weeks in rats and mice developing tumours throughout the body (Geiger et al., 2009; Newsholme et al., 2009) and 30 to 275 mg/kg leading to placental malformation in rats (Nishimura et al., 2013). In these animals, this high dosing would lead to agonists reaching the μM range, and therefore the nongenomic and off target effects of PPARβ/δ agonists become apparent. ...
... Dans le premier essai préclinique, le traitement avec cet agoniste a permis d'augmenté le métabolisme des lipides tout en protégeant les animaux contre le diabète de type II (Sprecher, 2007). Malgré le potentiel thérapeutique de ce traitement (Fan et al., 2017), les souris et les rats traités ont développé un cancer (Geiger et al., 2009). ...
Les mutations germinales activatrices de la voie RAS sont responsables de maladies rares regroupées sous le nom de RASopathies : le Syndrome de Noonan, le Syndrome de Noonan avec de Multiples Lentigines, la Neurofibromatose de type 1, le Syndrome de Malformations Capillaires et Malformations Artério-Veinseuses, le Syndrome Cardio-Facio-Cutané, le Syndrome de Legius et le Syndrome de Costello. Cette thèse s’intéresse au syndrome de Costello causé par une mutation hétérozygote de novo du gène HRAS. Ce syndrome est révélé dans les premiers mois de la vie et se caractérise par un retard de croissance postnatal, des traits du visage épais, un déficit intellectuel, des anomalies cutanées, ainsi qu’une prédisposition à développer des tumeurs. De plus, les patients atteints du syndrome de Costello développent une cardiomyopathie hypertrophique, de l’hypertension, une hypotonie et une myopathie d'origine moléculaire inconnue. En lien avec une association de malade et le service de génétique du CHU de Bordeaux, nous avons mené une exploration des anomalies protéomiques dans les tissus d’une souris modèle du syndrome de Costello ainsi que dans des fibroblastes de patients et des cellules modèles exprimant les formes mutées de HRASG12S et HRASG12A. Cette analyse globale et sans a priori a révélé des altérations au niveau du métabolisme énergétique et plus particulièrement de la composition des mitochondries. Le déficit fonctionnel des mitochondries, centrale énergétique du corps humain, a été caractérisé par des approches de biochimie, de bioénergétique et de biologie cellulaire. De plus, l’analyse des données ‘omiques’ a permis de suggérer une nouvelle hypothèse dans la physiopathologie du syndrome de Costello. Cette hypothèse considère l’implication d’un micro-ARN, le miR-221* dans l’inhibition du métabolisme oxydatif. Les analyses génétiques réalisées sur les cellules de patients et les cellules modèles ont démontré l’inhibition de l’expression de la protéine AMPK, un régulateur majeur du métabolisme mitochondrial, par le miR-221* sous le contrôle de HRASG12S et HRASG12A. Ces découvertes ont permis d’élaborer une stratégie thérapeutique visant à réduire la cardiomyopathie dans le syndrome de Costello. Les analyses précliniques effectuées sur les modèles cellulaires et le modèle murin ont permis d’évaluer l’efficacité d’une stimulation pharmacologique du métabolisme mitochondrial. Cette thèse révèle donc l’implication des mitochondries dans le syndrome de Costello et l’analyse moléculaire réalisée propose une série de données ‘Omiques’ qui permettront de progresser dans la compréhension de cette maladie rare.
... Glaxo Smith Kline (GSK) developed the agonist GW501516 (Endurobol), a promising compound that completed proof-of-concept clinical trials successfully for dyslipidaemia [8] and hypocholesteraemia [9]. Further studies revealed a potential link with tumor development [10,11], and any further clinical trial with GW501516 was suspended. ...
Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARβ/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ-regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL-6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL-6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS-induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co-incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production.
... Notably, the motions of the Ω loop in holo-PPAR complexes have also been suggested to affect the conformational populations of H12 [78,118,119]. During the last decade, evidence has accumulated on the toxicity of clinically employed PPARα and PPARγ classical agonists, such as certain fibrates [40,41], glitazones [42][43][44][45][46], and glitazars [47][48][49][50][51], as well as that of a PPARβ/δ classical agonist in rodents [120,121]. Combined with the knowledge of their common capacity for stabilization of H12, the frequently observed undesirable effects of these ligands could be interpreted as signs of a mechanism-based toxicity. Furthermore, as findings from the study of PPARγ demonstrate that classical agonism is not required to attain therapeutically relevant transcriptional outcomes (see Section 5), recent ligand development targeting PPARγ has aimed at avoiding ligands that strongly stabilize H12 [97,[122][123][124][125][126][127]. ...
The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARβ/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARβ/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARβ/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.
... [3][4][5] However safety concerns over GW501516 and potentially other drugs in the class have emerged. Of particular relevance are two abstracts from GSK showing that GW501516 causes cancer in rats 6 and mice 7 after 104 weeks of dosing. Although neither of these studies has been published as full peer-reviewed papers, these abstracts have been very influential. ...
... GW501516 has been included in the banned substance list since 2009 by the World Anti-Doping Agency, and was re-categorized as a 'hormone and metabolic modulator' drug in 2012. The clinical development of GW501516 was halted in 2007 after increased incidences of several cancer types were observed in rodents [209]. Recent developments in dual-and pan-PPAR agonists displayed therapeutic benefits for the complex and wide-range metabolic disorders [8]. ...
Skeletal muscle comprises 30–40% of the total body mass and plays a central role in energy homeostasis in the body. The deregulation of energy homeostasis is a common underlying characteristic of metabolic syndrome. Over the past decades, peroxisome proliferator-activated receptors (PPARs) have been shown to play critical regulatory roles in skeletal muscle. The three family members of PPAR have overlapping roles that contribute to the myriad of processes in skeletal muscle. This review aims to provide an overview of the functions of different PPAR members in energy homeostasis as well as during skeletal muscle metabolic disorders, with a particular focus on human and relevant mouse model studies.
... In preclinical trials, treatment with this agonist increased lipid metabolism and increased HDL levels, while preventing weight gain on a high-fat diet in mice, and protected animals against developing type II diabetes (8). Despite these promising indications that it could treat metabolic syndrome, treated mice and rats developed cancer and further development ceased (9). It is unclear whether activation of PPARδ or an off-target effect was responsible for carcinogenesis, and a more highly specific ligand is needed to enable researchers to definitively show whether PPARδ activation is a viable therapeutic target, or if activation is too dangerous. ...
... Furthermore, these mice develop age-dependent obesity and T2DM [51]. Further development of GW501516 for MetS was halted after preclinical studies reported that it could cause tumor development in several organs [52]. In a model of carbon tetrachloride-induced liver injury, GW501516-activated PPARβ/δ increased hepatic stellate cell proliferation in liver injuries, presumably via the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways, which would exacerbate fibrotic processes in injured livers [53]. ...
Introduction
Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise.
Areas covered
This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health.
Expert opinion
The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using ligands that simultaneously modulate the activity of more than one of these receptors is a major goal. This approach may provide essential knowledge for the development of dual or pan-PPAR agonists or antagonists as potential new health-promoting agents and for nutritional approaches to prevent metabolic diseases.
... 35 However, this needs to be treated with extreme caution for two key reasons. Firstly, PPARb drugs may negatively interact with current drugs 29 and secondly PPARb drugs are associated with increased risk of cancer 36,37 and warnings have been issued for their use, particularly directed at sports performance dosing where illicit procurement of drug maybe considered by athletes. ...
Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertension.
... Enhancement of PPARδ signaling has been suggested as an adjunct therapy to boost catabolism in visceral adipose tissue, perhaps in part through differentiation of adipose-resident MSCs to mitochondria-enriched small adipocytes [261]. To this end PPARδ agonists have been tested in clinical trials, but despite protective effects against obesity and diabetes, development was discontinued due to multiorgan cancer formation in animal models [262,263]. ...
Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan.
Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, a subsarcolemmal protein whose absence results in increased susceptibility of the muscle fiber membrane to contraction-induced injury. This results in increased calcium influx, oxidative stress, and mitochondrial dysfunction, leading to chronic inflammation, myofiber degeneration, and reduced muscle regenerative capacity. Fast glycolytic muscle fibers have been shown to be more vulnerable to mechanical stress than slow oxidative fibers in both DMD patients and DMD mouse models. Therefore, remodeling skeletal muscle toward a slower, more oxidative phenotype may represent a relevant therapeutic approach to protect dystrophic muscles from deterioration and improve the effectiveness of gene and cell-based therapies. The resistance of slow, oxidative myofibers to DMD pathology is attributed, in part, to their higher expression of Utrophin; there are, however, other characteristics of slow, oxidative fibers that might contribute to their enhanced resistance to injury, including reduced contractile speed, resistance to fatigue, increased capillary density, higher mitochondrial activity, decreased cellular energy requirements. This review focuses on signaling pathways and regulatory factors whose genetic or pharmacologic modulation has been shown to ameliorate the dystrophic pathology in preclinical models of DMD while promoting skeletal muscle fiber transition towards a slower more oxidative phenotype.
One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARor PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor’s structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.
Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells whose signaling controls inflammation and metabolism. However, there are great discrepancies in understanding the role of PPARβ/δ, having both anti- and pro-effects on inflammation. Understanding the PPARβ/δ mechanism of action may provide new molecular mechanisms for treating a variety of inflammatory-related diseases.
We studied the PPARβ/δ-regulation of LPS-induced inflammation of pulmonary artery, bronchi and parenchyma from rat, using different combinations of agonists (GW0742 or L-165402) and antagonists (GSK3787 or GSK0660). LPS-induced inflammation is largely regulated by PPARβ/δ in the pulmonary artery, but it is a minor factor in bronchi or parenchyma. Agonists do not significantly inhibit inflammation, but activates the PPARβ/δ induction mode of action. Surprisingly, co-incubation of the tissue with agonist plus antagonist shows anti-inflammatory effects and switches the PPARβ/δ mode of action from induction to trans-repression, indicating that the PPARβ/δ induction mode of action is pro-inflammatory and the trans-repression anti-inflammatory. Us of Computational chemistry methods indicates that PPARβ/δ agonists are predicted to form polar interactions with the residues His287, His413 and Tyr437 whilst PPARβ/δ antagonists form polar interactions with the residues Thr252 and Asn307. Further, our modelling indicates favorable binding energies and the feasibility of simultaneous binding of two ligands in the PPARβ/δ binding pocket. In summary, this study provides novel insight into the complex relationship between ligand binding profiles and functional outcomes in a rat lung inflammation model, which will help inform the design of novel therapies for inflammatory lung diseases.
The x-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPAR modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors, playing an important role in the regulation of glucose and lipids metabolism, inflammation response, proliferation and differentiation. Some drugs targeted on PPARs, such as lipid-lowering and antidiabetic drugs have been developed. Some PPAR agonists were found carcinogenic in animal experiments, including PPARα agonist fibrates, PPARγ agonist thiazolidinediones, PPARα/γ dual agonist compounds, and PPARδ agonist compounds for clinical development. PPARα agonist carcinogenicity is associated with PPAR receptor activation that regulates lipid metabolism, and leads to lipids abnormalities and increase by peroxisome oxidase in reactive oxygen species (ROS), causing DNA damage. Kupffer cells can generate ROS by NADPH oxidase that promotes hepatocyte proliferation and inhibition of apoptosis. PPARγ agonist carcinogenicity is generally caused by bladder stone. The carcinogenicity of PPAR agonists to humans has not been confirmed, but the carcinogenic potential of these drugs cannot be ignored.
Recent reports have shown that peroxisome proliferator-activated receptor delta (PPARD) plays an important role in different vascular processes suggesting that PPARD is a significant modulator of cardiovascular disease. This review will focus on PPARD in relation to cardiovascular risk factors based on cell, animal and human data. Mouse studies suggest that Ppard is an important metabolic modulator that may have implications for cardiovascular disease (CVD). Specific human PPARD gene variants show no clear association with CVD but interactions between variants and lifestyle factors might influence disease risk. During recent years, development of specific and potent PPARD agonists has also made it possible to study the effects of PPARD activation in humans. PPARD agonists seem to exert beneficial effects on dyslipidemia and insulin-resistant syndromes but safety issues have been raised due to the role that PPARD plays in cell proliferation. Thus, large long term outcome as well as detailed safety and tolerability studies are needed to evaluate whether PPARD agonists could be used to treat CVD in humans.
CKD-501 is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is effective for the treatment of diabetes. However, its carcinogenic potential remains controversial. The current carcinogenicity study was conducted over a period of 104 weeks in ICR mice. Three groups, each consisting of 60 male and 60 female mice, received oral CKD-501 dosages of 0.2, 1.0 or 6.0 mg kg(-1) day(-1) . The mortality rates of the male control, 0.2, 1.0 and 6.0 mg kg(-1) day(-1) treated groups were 60%, 68%, 58% and 67%, respectively and 57%, 68% and 67% in the female control, 0.2 and 1.0 mg kg(-1) day(-1) treated groups. It was 67% in the female 6.0 mg kg(-1) day(-1) treated group, which was terminated at week 98 due to its increased mortality rate. No significant treatment-related effects were observed on the survival rates, with the exception of females in the 6.0 mg kg(-1) day(-1) group. Body weights increased in females receiving 1.0 and 6.0 mg kg(-1) day(-1) due to the class effects of the PPARγ agonist. Differences were not found in hematology parameters between the CKD-501-treated groups and their corresponding controls, but the histopathological evidence did not reveal any findings attributed to CKD-501. Treated animals exhibited non-neoplastic findings (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy), but all of these were expected changes for this class of compound. There were no treatment-related neoplastic changes in this study. The results of this study therefore demonstrate a lack of carcinogenicity following oral administration of CKD-501 to ICR mice for 104 weeks. Copyright © 2013 John Wiley & Sons, Ltd.
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