PI3K inhibition reduces murine and human liver fibrogenesis in precisioncut liver slicesGore, E., Bigaeva, E., Oldenburger, A., Ook, K. Y., Rippmann, J. F., Schuppan, D., Boersema, M. & Olinga, P., Nov-2019, In : Biochemical Pharmacology. 169, 12 p., 113633.
Research output: Contribution to journal › Article › Academic › peer-review
Background: Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS).
Methods: Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 mu M for 48 h. PI3K pathway activation was assessed through protein kinase B (Akt) phosphorylation and antifibrotic efficacy was determined via a spectrum of fibrosis markers at the transcriptional and translational level.
Results: During incubation of PCTS the PI3K pathway was activated and incubation with omipalisib prevented Akt phosphorylation (IC50 = 20 and 1.5 nM for mouse and human, respectively). Viability of mouse and human liver PCTS was compromised only at the high concentration of 10 and 1-5 mu M, respectively. However, viability of jejunum PCTS decreased with 0.1 (mouse) and 0.01 mu M (human). Spontaneously increased fibrosis related genes and proteins were significantly and similarly suppressed in mouse and in human liver PCTS.
Conclusions: Omipalisib has antifibrotic properties in ex vivo mouse and human liver PCTS, but higher concentrations showed toxicity in jejunum PCTS. While the PI3K/mTOR pathway appears to be a promising target for the treatment of liver fibrosis, PCTS revealed likely side effects in the intestine at higher doses.
|Number of pages||12|
|Early online date||5-Sep-2019|
|Publication status||Published - Nov-2019|
- Precision-cut tissue slices, Liver fibrosis, Omipalisib, PI3K, Jejunum, CUT LIVER, EARLY-ONSET, FIBROSIS, MODEL, PROGRESSION, GSK2126458, BILIARY, TARGET, MATRIX