Raffaele, Marco, Kovacovicova, Kristina, Frohlich, Jan, Lo Re, Oriana, Giallongo, Sebastiano, Oben, Jude A, Faldyna, Martin, Leva, Lenka, Giannone, Antonino Giulio, Cabibi, Daniela et al (show 1 more authors)
(2021)
Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin.
CELL COMMUNICATION AND SIGNALING, 19 (1).
44-.
Abstract
<h4>Background</h4>Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown.<h4>Methods</h4>Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches.<h4>Results</h4>Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal.<h4>Conclusions</h4>In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Senolytics, Liver diseases, Inflammation, Cancer, Obesity |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 24 Jan 2023 09:29 |
| Last Modified: | 24 Jan 2023 09:29 |
| DOI: | 10.1186/s12964-021-00731-0 |
| Open Access URL: | https://doi.org/10.1186/s12964-021-00731-0 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3167841 |
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