title: Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: impact on sorafenib cytotoxicity.
abstract: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of these transporters. Genistein (GNT) is a phytoestrogen abundant in soybean that exerts its genomic effects through Estrogen-Receptors and Pregnane-X-Receptor (PXR), which are involved in the regulation of the above-mentioned transporters. We evaluated the effect of GNT on the expression and activity of P-gp, MRP2, MRP3 and BCRP in HCC-derived HepG2 cells. GNT (at 1.0 and 10 μM) increased P-gp and MRP2 protein expression and activity, correlating well with an increased resistance to sorafenib cytotoxicity as detected by the methylthiazole tetrazolium (MTT) assay. GNT induced P-gp and MRP2 mRNA expression at 10 but not at 1.0 μM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 μM GNT was prevented by cycloheximide, suggesting translational regulation. Downregulation of expression of the miR-379 by GNT could be associated with translational regulation of MRP2. Silencing of PXR abolished P-gp induction by GNT (at 1.0 and 10 μM) and MRP2 induction by GNT (only at 10 μM), suggesting partial mediation of GNT effects by PXR. Taken together, the data suggest the possibility of nutrient-drug interactions leading to enhanced chemoresistance in HCC when GNT is ingested with soy rich diets or dietary supplements.
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rigalli
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Nadia
authors.initials: N
authors.lastname: Ciriaci
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Agostina
authors.initials: A
authors.lastname: Arias
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: María Paula
authors.initials: MP
authors.lastname: Ceballos
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Silvina Stella Maris
authors.initials: SS
authors.lastname: Villanueva
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Marcelo Gabriel
authors.initials: MG
authors.lastname: Luquita
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Aldo Domingo
authors.initials: AD
authors.lastname: Mottino
authors.affiliation: Institute of Pharmacological Investigations (ININFA-CONICET), Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carolina Inés
authors.initials: CI
authors.lastname: Ghanem
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: Viviana Alicia
authors.initials: VA
authors.lastname: Catania
authors.affiliation: Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.
authors.forename: María Laura
authors.initials: ML
authors.lastname: Ruiz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D048789:Phytoestrogens / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C561022:MIRN379 microRNA, human; D026901:Membrane Transport Proteins; D035683:MicroRNAs; D010671:Phenylurea Compounds; D048789:Phytoestrogens; D012333:RNA, Messenger; D009536:Niacinamide; D000077157:Sorafenib; D019833:Genistein