Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn's Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells.

Dominika Kovács,Viola Bagóné Vántus,Eszter Vámos,Ferenc Gallyas,Nikoletta Kálmán,Balázs Radnai,Rudolf Schicho,Mariaurea Matias Sarandy

doi:10.1155/2021/7308897

Dominika Kovács, Viola Bagóné Vántus + Show 6 more

Open Access

https://doi.org/10.1155/2021/7308897

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Abstract

Crohn's disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1β and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H2O2-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn's disease.

Highlights

Inflammatory bowel disease (IBD) is a chronic and remitting inflammatory disease of the gut
We investigated whether olaparib, a PARP inhibitor used in human cancer therapy, has a beneficial effect in a Crohn’s disease (CD) mouse model and, whether it could be repurposed for CD treatment
We explicitly focused on the epithelial barrier function, cell survival, and bioenergetics; we used a Caco-2 monolayer as an in vitro model of intestinal epithelial barrier [46]

Summary

Introduction

Inflammatory bowel disease (IBD) is a chronic and remitting inflammatory disease of the gut. More than 1 million inhabitants in the USA and approximately 2.5 million in Europe suffer from IBD, and its incidence is permanently rising [1]. IBD exhibits two main forms, namely, ulcerative colitis (UC) and Crohn’s disease (CD), and it appears in flare-up and remission phases [2]. UC and CD are two distinct forms of IBD, they share the phenomenon of epithelial barrier dysfunction. Barrier failure often results in increased intestinal permeability, a condition called “leaky gut” [3].

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