Abstract
BackgroundLiver 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). MethodsMurine 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. ResultsDuring 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. ConclusionsOmipalisib 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.
Highlights
Liver fibrosis is a chronic disease caused by continuous injury, with a high prevalence worldwide
We demonstrated the antifibrotic effect and toxicity of omipalisib, a Phosphatidylinositol 3-kinase (PI3K) paninhibitor, in a murine and human ex vivo model (PCTS), mimicking early-onset and end-stage liver fibrosis and normal intestine
Increased PI3K activity is associated with hyperproliferation and cancer [15], PI3K pan-inhibitors were developed as chemotherapy [13]
Summary
Liver fibrosis is a chronic disease caused by continuous injury, with a high prevalence worldwide. Several Class I PI3K inhibitors were developed and are currently investigated in preclinical or clinical studies These compounds include pan-isoform inhibitors, which can inhibit all four catalytic isoforms of Class I PI3K, and isoform-specific inhibitors [34]. These compounds show promising results and can be fairly well tolerated in patients, there are toxic side effects that have to be taken into account. We evaluated the toxicity and antifibrotic effect of a Class I PI3K pan-inhibitor of the catalytic subunit, omipalisib (GSK2126458, GSK458), in murine and human ex vivo precision-cut tissue slices (PCTS), a model for early onset and end stage of fibrosis, with human PCTS serving as a bridge towards human studies
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