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

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.

Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury

“…Thus, the function and trafficking of neutrophils may be mainly influenced by the effects of the PARP inhibitors on other cell types, while the function and trafficking of mononuclear cells may be affected by PARP through a combination of effects on these cells (as well as on their environment). Differential effects of olaparib on neutrophils vs. mononuclear cells have also recently been noted in a model of colitis: in this model, neutrophilia was not affected by the PARP inhibitor, while the changes in lymphocyte and monocyte numbers were partially normalized by the PARP inhibitor [ 43 ]. In another study investigating various white blood cell types from myelodysplastic patients, olaparib more significantly affected cells of the myeloid than of the lymphoid lineage [ 49 ].…”

“…The mechanism by which PARP inhibitors protect cells or tissues from oxidative damage is complex. In vitro, in simple oxidant-induced cell injury models, the simplest explanation for the cytoprotective effects of PARP inhibitors follows the “Berger hypothesis”, whereby PARP inhibitors prevent the NAD + and ATP depletion that is elicited by PARP over-activation when PARP recognizes multiple DNA strand breaks [ 1 , 2 , 5 , 38 , 39 , 40 , 41 , 42 , 43 ], while in vivo, additional effects (e.g., inhibition of pro-inflammatory mediator production, inhibition of immune cell infiltration into the affected tissues, interruption of positive feedforward cycles of inflammation and organ injury) may also contribute [ 1 , 5 , 44 , 45 , 46 , 47 , 48 ]. Under such conditions, we hypothesize that PARP inhibition maintains overall improved cell viability and may also maintain a better cellular bioenergetic profile, which, in turn, may help maintain the activity of various DNA repair enzymes.…”

“…The underlying mechanisms are likely multiple: they may involve direct cytoprotective effects, regulation of various inflammatory mediators, and—as a consequence of these—suppression of inflammatory cell infiltration and attenuation of various self-amplifying cycles of cell and tissue injury. These mechanisms have already been characterized extensively in various in vitro and in vivo models using various classes of PARP inhibitors, including clinically approved ones such as olaparib [ 1 , 2 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury

“…Attempts to modify IEC metabolism, using P110, a small peptide inhibitor of mitochondrial fission 172 , or olaparib, a clinically applied PARP inhibitor improving mitochondrial function 173 , already succeeded in reducing chemically induced colitis in mice. Additionally, established drugs like 5-amino salicylic acid, that alters mitochondrial metabolism 174 , might already be efficient by targeting epithelial metabolism.…”

Improvement of loperamide-hydrochloride-induced intestinal motility disturbance by Platycodon grandiflorum polysaccharides through effects on gut microbes and colonic serotonin

“…Fructose and glucose are respectively transported into cells by phosphoenolpyruvate-sugar phosphotransferase (PTS) system to produce fructose-6-phosphate and glucose-6-phosphate, respectively, for glycolysis( Goh and Klaenhammer, 2015 ). The glycolytic pathway of colon is closely related to maintaining the integrity of intestinal wall cells and energy supply( Kovács et al., 2021 ). In summary, the phosphotransferase system plays a significant role in affecting the energy source of intestinal peristalsis.…”