PMID- 25781341 OWN - NLM STAT- MEDLINE DCOM- 20160216 LR - 20220330 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 3 DP - 2015 TI - Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: impact on sorafenib cytotoxicity. PG - e0119502 LID - 10.1371/journal.pone.0119502 [doi] LID - e0119502 AB - 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 muM) 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 muM concentration suggesting a different pattern of regulation depending on the concentration. Induction of both transporters by 1.0 muM 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 muM) and MRP2 induction by GNT (only at 10 muM), 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. FAU - Rigalli, Juan Pablo AU - Rigalli JP AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Ciriaci, Nadia AU - Ciriaci N AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Arias, Agostina AU - Arias A AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Ceballos, Maria Paula AU - Ceballos MP AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Villanueva, Silvina Stella Maris AU - Villanueva SS AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Luquita, Marcelo Gabriel AU - Luquita MG AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Mottino, Aldo Domingo AU - Mottino AD AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Ghanem, Carolina Ines AU - Ghanem CI AD - Institute of Pharmacological Investigations (ININFA-CONICET), Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina. FAU - Catania, Viviana Alicia AU - Catania VA AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. FAU - Ruiz, Maria Laura AU - Ruiz ML AD - Institute of Experimental Physiology (IFISE-CONICET), Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150317 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antineoplastic Agents) RN - 0 (MIRN379 microRNA, human) RN - 0 (Membrane Transport Proteins) RN - 0 (MicroRNAs) RN - 0 (Phenylurea Compounds) RN - 0 (Phytoestrogens) RN - 0 (RNA, Messenger) RN - 25X51I8RD4 (Niacinamide) RN - 9ZOQ3TZI87 (Sorafenib) RN - DH2M523P0H (Genistein) SB - IM MH - Antineoplastic Agents/pharmacology MH - Apoptosis/*drug effects MH - Blotting, Western MH - Carcinoma, Hepatocellular/drug therapy/metabolism/*pathology MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/*drug effects MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Genistein/*pharmacology MH - Humans MH - Liver Neoplasms/drug therapy/metabolism/pathology MH - Membrane Transport Proteins/drug effects/genetics/*metabolism MH - MicroRNAs/genetics MH - Niacinamide/*analogs & derivatives/pharmacology MH - Phenylurea Compounds/*pharmacology MH - Phytoestrogens/pharmacology MH - RNA, Messenger/genetics MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - Sorafenib MH - Tumor Cells, Cultured PMC - PMC4364073 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/03/18 06:00 MHDA- 2016/02/18 06:00 PMCR- 2015/03/17 CRDT- 2015/03/18 06:00 PHST- 2014/10/16 00:00 [received] PHST- 2015/01/13 00:00 [accepted] PHST- 2015/03/18 06:00 [entrez] PHST- 2015/03/18 06:00 [pubmed] PHST- 2016/02/18 06:00 [medline] PHST- 2015/03/17 00:00 [pmc-release] AID - PONE-D-14-46562 [pii] AID - 10.1371/journal.pone.0119502 [doi] PST - epublish SO - PLoS One. 2015 Mar 17;10(3):e0119502. doi: 10.1371/journal.pone.0119502. eCollection 2015.