PPARγ Agonists in Combination Cancer Therapies

2020 ◽  
Vol 20 (3) ◽  
pp. 197-215
Author(s):  
Piotr Mrowka ◽  
Eliza Glodkowska-Mrowka
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Potential ◽  
Pharmacological Therapy ◽  
Treatment Modalities ◽  
Peroxisome Proliferator ◽  
Tumoricidal Activity ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anticancer Efficacy ◽  
Pparγ Agonists

: Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor acting as a transcription factor involved in the regulation of energy metabolism, cell cycle, cell differentiation, and apoptosis. These unique properties constitute a strong therapeutic potential that place PPARγ agonists as one of the most interesting and widely studied anticancer molecules. : Although PPARγ agonists exert significant, antiproliferative and tumoricidal activity in vitro, their anticancer efficacy in animal models is ambiguous, and their effectiveness in clinical trials in monotherapy is unsatisfactory. However, due to pleiotropic effects of PPARγ activation in normal and tumor cells, PPARγ ligands interact with many antitumor treatment modalities and synergistically potentiate their effectiveness. The most spectacular example is a combination of PPARγ ligands with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In this setting, PPARγ activation sensitizes leukemic stem cells, resistant to any previous form of treatment, to targeted therapy. Thus, this combination is believed to be the first pharmacological therapy able to cure CML patients. : Within the last decade, a significant body of data confirming the benefits of the addition of PPARγ ligands to various antitumor therapies, including chemotherapy, hormonotherapy, targeted therapy, and immunotherapy, has been published. Although the majority of these studies have been carried out in vitro or animal tumor models, a few successful attempts to introduce PPARγ ligands into anticancer therapy in humans have been recently made. In this review, we aim to summarize shines and shadows of targeting PPARγ in antitumor therapies.

scholarly journals Enhanced Therapeutic Potential of the Secretome Released from Adipose-Derived Stem Cells by PGC-1α-Driven Upregulation of Mitochondrial Proliferation

2019 ◽  
Vol 20 (22) ◽  
pp. 5589
Author(s):  
Jaeim Lee ◽  
Ok-Hee Kim ◽  
Sang Chul Lee ◽  
Kee-Hwan Kim ◽  
Jin Sun Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Therapeutic Potential ◽  
Tissue Expression ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Adipose Derived Stem Cells ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor λ coactivator 1α (PGC-1α) is a potent regulator of mitochondrial biogenesis and energy metabolism. In this study, we investigated the therapeutic potential of the secretome released from the adipose-derived stem cells (ASCs) transfected with PGC-1α (PGC-secretome). We first generated PGC-1α-overexpressing ASCs by transfecting ASCs with the plasmids harboring the gene encoding PGC-1α. Secretory materials released from PGC-1α-overexpressing ASCs were collected and their therapeutic potential was determined using in vitro (thioacetamide (TAA)-treated AML12 cells) and in vivo (70% partial hepatectomized mice) models of liver injury. In the TAA-treated AML12 cells, the PGC-secretome significantly increased cell viability, promoted expression of proliferation-related markers, such as PCNA and p-STAT, and significantly reduced the levels of reactive oxygen species (ROS). In the mice, PGC-secretome injections significantly increased liver tissue expression of proliferation-related markers more than normal secretome injections did (p < 0.05). We demonstrated that the PGC-secretome does not only have higher antioxidant and anti-inflammatory properties, but also has the potential of significantly enhancing liver regeneration in both in vivo and in vitro models of liver injury. Thus, reinforcing the mitochondrial antioxidant potential by transfecting ASCs with PGC-1α could be one of the effective strategies to enhance the therapeutic potential of ASCs.

scholarly journals Peroxisome Proliferator-Activated Receptor-γ Antagonizes LOX-1-Mediated Endothelial Injury by Transcriptional Activation of miR-590-5p

PPAR Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Lei Xu ◽  
Gang Zhao ◽  
Hong Zhu ◽  
Shijun Wang ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Umbilical Vein ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the major receptors expressed on the endothelium of arterial wall with a key role in endothelial dysfunction and the development of atherosclerosis. Recent evidence suggested that LOX-1 is upregulated under the condition of insulin resistance and could be suppressed by the antidiabetic drugs. We previously also confirmed that Thiazolidinedione (TZD) has the inhibitory effect on LOX-1 in ox-LDL-induced endothelial cells. However, the underlying mechanism is unclear. Here we showed that Rosiglitazone treatment significantly attenuated the expressions of LOX-1, ICAM-1, VCAM-1, p47phox, and the atherosclerotic lesions in ApoE-/- mice with high-fat diet. In vitro, we revealed that Rosiglitazone inhibited LOX-1 by regulating miR-590-5p. Ox-LDL-mediated ICAM-1, VCAM-1, and p47phox were significantly reduced by Rosiglitazone, but all reversed after pretreating the cells with antagomiR-590-5p. Induction with Rosiglitazone activated PPAR-γ and promoted its nuclear translocation in cultured human umbilical vein endothelial cells (HUVECs). The nuclear PPAR-γ upregulated the miR-590-5p level through binding to its transcriptional promoter region. Retaining PPAR-γ in cytoplasm by transfecting with PPAR-γ⊿NLS plasmid in HUVECs failed to activate miR-590-5p. Mutation of the promoter region of PPAR-γ also reduced the miR-590-5p promoter luciferase activity. Collectively, these data indicated that PPAR-γ may have the therapeutic potential in atherosclerosis via the transcriptional regulation of miR-590-5p in endothelial cells.

scholarly journals The Role of PPARγin the Transcriptional Control by Agonists and Antagonists

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Tamotsu Tsukahara
Keyword(s):  
Transcriptional Repression ◽  
Transcriptional Control ◽  
Thyroid Hormone Receptor ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclic Phosphatidic Acid

In recent years, peroxisome proliferator-activated receptor gamma (PPARγ) has been reported to be a target for the treatment of type II diabetes. Furthermore, it has received attention for its therapeutic potential in many other human diseases, including atherosclerosis, obesity, and cancers. Recent studies have provided evidence that the endogenously produced PPARγ antagonist, 2,3-cyclic phosphatidic acid (cPA), which is similar in structure to lysophosphatidic acid (LPA), inhibits cancer cell invasion and metastasisin vitroandin vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the corepressor protein, silencing mediator of retinoic acid and thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. We then analyzed the molecular mechanism of cPA's action on PPARγ. In this paper, we summarize the current knowledge on the mechanism of PPARγ-mediated transcriptional activity and transcriptional repression in response to novel lipid-derived ligands, such as cPA.

scholarly journals Peroxisome proliferator-activated receptor-γ in cystic fibrosis lung epithelium

2008 ◽  
Vol 295 (2) ◽  
pp. L303-L313 ◽  
Author(s):  
Aura Perez ◽  
Anna M. van Heeckeren ◽  
David Nichols ◽  
Sanhita Gupta ◽  
Jean F. Eastman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Acute Infection ◽  
Airway Epithelial Cells ◽  
Peroxisome Proliferator ◽  
Airway Epithelial ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonists

The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NF-κB activation. Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits NF-κB activity and is reported to be reduced in CF. If PPARγ participates in regulatory dysfunction in the CF lung, perhaps PPARγ ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPARγ expression and binding to NF-κB at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNFα/IL-1β. An animal model of CF was used to evaluate the potential of PPARγ agonists as therapeutic agents in vivo. In vitro, PPARγ agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNFα/IL-1β stimulation. Less NF-κB bound to PPARγ in CF than normal cells, in two different assays; PPARγ agonists abrogated this reduction. PPARγ bound less to its target DNA sequence in CF cells. To test the importance of the reported PPARγ inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPARγ agonists in reducing IL-8 secretion. In vivo, administration of PPARγ agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wild-type, mice. In summary, PPARγ inhibits the inflammatory response in CF, at least in part by interaction with NF-κB in airway epithelial cells. PPARγ agonists may be therapeutic in CF.

scholarly journals Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease

2015 ◽  
Vol 309 (10) ◽  
pp. L1219-L1228 ◽  
Author(s):  
Chantal Donovan ◽  
Simon R. Bailey ◽  
Jenny Tran ◽  
Gertruud Haitsma ◽  
Zaridatul A. Ibrahim ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Allergen Challenge ◽  
Peroxisome Proliferator ◽  
Small Airways ◽  
Peroxisome Proliferator Activated Receptor ◽  
Complete Relaxation ◽  
Adrenoceptor Agonists ◽  
Precision Cut Lung Slices

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and β-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPARγ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-Δ12,14-prostaglandin J2 (15-deoxy-PGJ2)] or β-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPARγ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized ( days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than β-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than β-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPARγ-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to β-adrenoceptor agonists is limited.

scholarly journals Development of an In Vitro Screening Platform for the Identification of Partial PPARγ Agonists as a Source for Antidiabetic Lead Compounds

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2431 ◽  
Author(s):  
Lars Porskjær Christensen ◽  
Rime Bahij El-Houri
Keyword(s):  
Side Effects ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
In Silico Docking ◽  
Lead Compounds ◽  
Ppar Γ ◽  
Pparγ Agonists ◽  
Screening Platform

Type 2 diabetes (T2D) is a metabolic disorder where insulin-sensitive tissues show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to hyperglycaemia. Peroxisome proliferator-activated receptor (PPAR)γ plays an important role in lipid and glucose homeostasis and is one of the targets in the discovery of drugs against T2D. Activation of PPARγ by agonists leads to a conformational change in the ligand-binding domain, a process that alters the transcription of several target genes involved in glucose and lipid metabolism. Depending on the ligands, they can induce different sets of genes that depends of their recruitment of coactivators. The activation of PPARγ by full agonists such as the thiazolidinediones leads to improved insulin sensitivity but also to severe side effects probably due to their behavior as full agonists. Partial PPARγ agonists are compounds with diminished agonist efficacy compared to full agonist that may exhibit the same antidiabetic effect as full agonists without inducing the same magnitude of side effects. In this review, we describe a screening platform for the identification of partial PPARγ agonists from plant extracts that could be promising lead compounds for the development of antidiabetic drugs. The screening platform includes a series of in vitro bioassays, such as GU in adipocytes, PPARγ-mediated transactivation, adipocyte differentiation and gene expression as well as in silico docking for partial PPARγ agonism.

Transcriptome analysis of porcine endometrium after LPS-induced inflammation: effects of the PPAR-gamma ligands in vitro†

2020 ◽  
Author(s):  
Karol Mierzejewski ◽  
Łukasz Paukszto ◽  
Aleksandra Kurzyńska ◽  
Zuzanna Kunicka ◽  
Jan Paweł Jastrzębski ◽  
...  
Keyword(s):  
Luteal Phase ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Rna Seq ◽  
Peroxisome Proliferator Activated Receptor ◽  
Genes Expression ◽  
Microbial Infections ◽  
Pparγ Agonists ◽  
Vitro Effect

Abstract Female fertility depends greatly on the capacity of the uterus to recognize and eliminate microbial infections, a major reason of inflammation in the endometrium in many species. This study aimed to determine the in vitro effect of peroxisome proliferator-activated receptor gamma (PPARγ) ligands on the transcriptome genes expression and alternative splicing in the porcine endometrium in the mid-luteal phase of the estrous cycle during LPS-stimulated inflammation using RNA-seq technology. The endometrial slices were incubated in vitro in the presence of LPS and PPARγ agonists—PGJ2 or pioglitazone and antagonist—T0070907. We identified 222, 3, 4, and 62 differentially expressed genes after LPS, PGJ2, pioglitazone, or T0070907 treatment, respectively. In addition, we detected differentially alternative spliced events: after treatment with LPS-78, PGJ2-60, pioglitazone-52, or T0070907-134. These results should become a basis for further studies explaining the mechanism of PPARγ action in the reproductive system in pigs.

scholarly journals Potential role for peroxisome proliferator-activated receptor γ in regulating luteal lifespan in the rat

Reproduction ◽  
2007 ◽  
Vol 133 (1) ◽  
pp. 187-196 ◽  
Author(s):  
Nicole Tinfo ◽  
Carolyn Komar
Keyword(s):  
Corpora Lutea ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Luteal Cells ◽  
Progesterone Production ◽  
Chain Cleavage ◽  
Major Player ◽  
Luteal Tissue ◽  
Pparγ Agonists

Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to stimulate progesterone production by bovine luteal cells. We previously reported higher expression of PPARγ in old compared with new luteal tissue in the rat. The following studies were conducted to determine the role of PPARγ in rat corpora lutea (CL) and test the hypothesis that PPARγ plays a role in the metabolism of progesterone and/or luteal lifespan. Ovaries were removed from naturally cycling rats throughout the estrous cycle, and pseudopregnant rats. mRNA for PPARγ and P450 side-chain cleavage (SCC) was localized in luteal tissue byin situhybridization, and protein corresponding to PPARγ and macrophages identified by immunohistochemistry. Luteal tissue was cultured with agonists (ciglitazone, prostaglandin J2) or an antagonist (GW-9662) of PPARγ. Progesterone was measured in media by RIA and levels of mRNA for 20α-hydroxysteriod dehydrogenase (HSD) and bcl-2 were measured in luteal tissue after culture by RT-PCR. An inverse relationship existed between the expression of mRNA for SCC and PPARγ. There was no effect of PPARγ agonists or the antagonist on luteal progesterone productionin vitro, or levels of mRNA for 20α-HSD. PPARγ protein was localized to the nuclei of luteal cells and did not correspond with the presence of macrophages. In new CL, ciglitazone decreased mRNA for bcl-2 on proestrus, estrus, and metestrus. Interestingly, GW-9662 also decreased mRNA for bcl-2 on proestrus and diestrus in old and new CL, and on metestrus in new CL. These data indicate that PPARγ is not a major player in luteal progesterone production or metabolism but may be involved in regulating luteal lifespan.

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