Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib plus quercetin

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Authors	RAFFAELE Marco KOVAČOVICOVÁ Kristína FROHLICH Jan LO RE Oriana GIALLONGO Sebastiano OBEN J. A. FALDYNA Martin LEVA Lenka GIANNONE Antonino Giulio CABIBI Daniela VINCIGUERRA Manlio
Year of publication	2021
Type	Article in Periodical
Magazine / Source	Cell Communication and Signaling
MU Faculty or unit	Faculty of Medicine
Citation
Web	https://biosignaling.biomedcentral.com/articles/10.1186/s12964-021-00731-0
Doi	http://dx.doi.org/10.1186/s12964-021-00731-0
Keywords	Senolytics; Liver diseases; Inflammation; Cancer; Obesity
Description	Background 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 beta-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. Methods 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. Results 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. Conclusions In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC.
Related projects:	Biomedicínské vědy