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Biochem Pharmacol. 2019 Sep 5;169:113633. doi: 10.1016/j.bcp.2019.113633. [Epub ahead of print]

PI3K inhibition reduces murine and human liver fibrogenesis in precision-cut liver slices.

Author information

1
Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands.
2
Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss 88397, Germany.
3
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Obere Zahlbacherstraße 63, Mainz 55131, Germany.
4
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Obere Zahlbacherstraße 63, Mainz 55131, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 330 Brookline Avenue, MA 02215, USA.
5
Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713AV, The Netherlands. Electronic address: p.olinga@rug.nl.

Abstract

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 μM 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 μM, respectively. However, viability of jejunum PCTS decreased with 0.1 (mouse) and 0.01 μM (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.

KEYWORDS:

Jejunum; Liver fibrosis; Omipalisib; PI3K; Precision-cut tissue slices

PMID:
31494146
DOI:
10.1016/j.bcp.2019.113633
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