Structure–activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Okazaki, Satoshi; Shioi, Ryuta; Noguchi‐Yachide, Tomomi; Ishikawa, Minoru; Makishima, Makoto; Hashimoto, Yuichi; Yamaguchi, Takao

doi:10.1016/j.bmc.2016.08.067

Cited by 9 publications

(9 citation statements)

References 13 publications

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“…In response to ligand activation, these receptors regulate adipogenesis, lipid metabolism, and glucose homeostasis. Furthermore, they are involved in inflammatory processes, proliferation, and cancer metabolism [17][18][19]. These receptors can be activated by natural ligands, such as fatty acids or prostaglandins, as well as by synthetic ligands [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

Kazberuk

Chalecka

Pałka

et al. 2022

IJMS

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPARγ, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPARγ expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX–PPARγ axis can be considered a novel approach for breast cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

Kazberuk

Chalecka

Pałka

et al. 2022

IJMS

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“…Quantitative Structure Activity Relationship (QSAR) 9 study was performed on a dataset by means of Multiple Linear Regressions (MLR) 10 using software SPSS. 11 The dataset consists of a set of 71 derivatives of Phenyl Propanoic Acid (PPA) out of which 46 active molecules (Fig.…”

Section: Methodsmentioning

confidence: 99%

In-silico Analysis of Phenyl Propanoic Acid Derivatives to Design Potent Peroxisome Proliferator-activated Receptor (PPAR) Dual Agonists for Type 2 Diabetes mellitus Therapy

Verma¹,

Chouhan²

2018

Orient. J. Chem

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Background: Type 2 Diabetes mellitus (T2DM) is an enfeeble and thriving disorder outlined by the hyperglycemia. The exponentially rising prevalence of T2DM, serves a major dilemma to public health and is marked by a fall in reactiveness of the tissues with respect to insulin that can be restored by the stimulation of Peroxisome Proliferator-Activated Receptors (PPARs). Identification of the structural features of ligands is performed in this study, which can help in modelling potent molecules to activate PPARs and normalize hyperglycaemia. Multiple Linear Regression (MLR) analysis was performed on the dataset of the PPAR's agonists followed by docking analysis and Molecular Dynamics Simulation (MDS). A 'sum-model' is developed to design PPAR activators by adding the activities (EC 50 ) of the ligands contrary to individual subtypes (PPARα and PPARγ) and using it as dependent parameter followed by validation using a test set of molecules, calculating the modified r 2 and 'Leave One-Out' (LOO) method. The sum-model represents the optimum statistical outcome with R 2 = 0.745 and R2pred = 0.838 while the corresponding values for the other two models are 0.747 and 0.732 for α-model, 0.600 and 0.677 for γ-model respectively. Docking analysis revealed that hydrogen bonding interactions are fundamental feature essential for the interaction among PPARs and Phenyl Propanoic Acid (PPA) derivatives. Docking of the most active compound to the proteins was followed by dynamically stabilizing the docked complexes of the PPARγ (1FM9) and PPARα (1K7L). The molecule PPARγ was found to stabilize at 2717ps having an RMSD value of 0.607nm while PPARα stabilized at 4500ps with an RMSD value of 1.1213 nm. The potential energy, kinetic energy and total energy of the 1FM9 at 2717ps were found to be -543611 kj/mol, 96167 kj/ mol and -441916 kj/mol, respectively, and that of 1K7L at 4500ps are found to be -2.995595 kj/mol, 542616 kj/mol and -2.45353 kj/mol respectively.

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“…PPARs can regulate the transcription of multiple genes in response to activation by natural or synthetic ligands. Although PPARs regulate lipid metabolism, glucose homeostasis, and adipogenesis [36], they can also affect inflammation, proliferation, differentiation, and carcinogenesis [37,38]. Activation of PPAR requires heterodimerization with retinoid X receptors (RXR) to form PPAR/RXR complex which binds to specific DNA fragment called PPAR response element (PPRE) in a target gene [39].…”

Section: Molecular Polymorphism and Function Of Pparmentioning

confidence: 99%

A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor

et al. 2020

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Although pharmaco-epidemiological studies provided evidence for the anticancer potential of non-steroidal anti-inflammatory drugs (NSAIDs), the mechanism of their anti-cancer activity is not known. Several lines of evidence suggest that proline dehydrogenase/proline oxidase (PRODH/POX) may represent a target for NSAIDs-dependent anti-cancer activity. PRODH/POX catalyzes conversion of proline into Δ1-pyrroline-5-carboxylate releasing ATP or reactive oxygen species for autophagy/apoptosis. Since NSAIDs are ligands of peroxisome proliferator-activated receptor (PPARs) and PPARs are implicated in PRODH/POX-dependent apoptosis we provided a hypothesis on the mechanism of NSAIDs-induced apoptosis in cancer cells.

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Structure–activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Cited by 9 publications

References 13 publications

Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

In-silico Analysis of Phenyl Propanoic Acid Derivatives to Design Potent Peroxisome Proliferator-activated Receptor (PPAR) Dual Agonists for Type 2 Diabetes mellitus Therapy

A novel plausible mechanism of NSAIDs-induced apoptosis in cancer cells: the implication of proline oxidase and peroxisome proliferator-activated receptor

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