Author, as appears in the article.: Verdura, Sara; Antonio Encinar, Jose; Fernandez-Arroyo, Salvador; Joven, Jorge; Cuyas, Elisabet; Bosch-Barrera, Joaquim; Menendez, Javier A.;
Department: Medicina i Cirurgia
URV's Author/s: FERNANDEZ ARROYO, SALVADOR / Joven Maried, Jorge
Keywords: Statins Silibinin Progression Milk thistle Mechanism Lung-cancer Lorlatinib Lipidomics Lines In-vitro model Hypertriglyceridemia Hypercholesteremia Huh-7 Heparg cells Cyp3a4 Crizotinib Complex
Abstract: The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug-drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.
Thematic Areas: Zootecnia / recursos pesqueiros Spectroscopy Saúde coletiva Química Psicología Physical and theoretical chemistry Organic chemistry Odontología Nutrição Molecular biology Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Interdisciplinar Inorganic chemistry Geociências Farmacia Engenharias iv Engenharias ii Engenharias i Educação física Computer science applications Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Ciência da computação Chemistry, multidisciplinary Catalysis Biotecnología Biodiversidade Biochemistry & molecular biology Astronomia / física
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: jorge.joven@urv.cat
Author identifier: 0000-0003-2749-4541
Record's date: 2023-02-19
Papper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://www.mdpi.com/1422-0067/23/17/9986
Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: International Journal Of Molecular Sciences. 23 (17):
APA: Verdura, Sara; Antonio Encinar, Jose; Fernandez-Arroyo, Salvador; Joven, Jorge; Cuyas, Elisabet; Bosch-Barrera, Joaquim; Menendez, Javier A.; (2022). Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells. International Journal Of Molecular Sciences, 23(17), -. DOI: 10.3390/ijms23179986
Article's DOI: 10.3390/ijms23179986
Entity: Universitat Rovira i Virgili
Journal publication year: 2022
Publication Type: Journal Publications
Repositori URV