title: New Approach for Treatment of Primary Liver Tumors: The Role of Quercetin.
abstract: Hepatocellular carcinoma (HCC) is the most common primary liver tumor (PLT), with cholangiocarcinoma (CC) being the second most frequent. Glucose transporter 1 (GLUT-1) expression is increased in PLTs and therefore it is suggested as a therapeutic target. Flavonoids, like quercetin, are GLUT-1 competitive inhibitors and may be considered as potential therapeutic agents for PLTs. The objective of this study was evaluation of quercetin anticancer activity in three human HCC cell lines (HepG2, HuH7, and Hep3B2.1-7) and in a human CC cell line (TFK-1). The possible synergistic effect between quercetin and sorafenib, a nonspecific multikinase inhibitor used in clinical practice in patients with advanced HCC, was also evaluated. It was found that in all the cell lines, quercetin induced inhibition of the metabolic activity and cell death by apoptosis, followed by increase in BAX/BCL-2 ratio. Treatment with quercetin caused DNA damage in HepG2, Hep3B2.1-7, and TFK-1 cell lines. The effect of quercetin appears to be independent of P53. Incubation with quercetin induced an increase in GLUT-1 membrane expression and a consequent reduction in the cytoplasmic fraction, observed as a decrease in (18)F-FDG uptake, indicating a GLUT-1 competitive inhibition. The occurrence of synergy when sorafenib and quercetin were added simultaneously to HCC cell lines was noticed. Thus, the use of quercetin seems to be a promising approach for PLTs through GLUT-1 competitive inhibition.
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Brito
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|c Faculty of Sciences and Technology, University of Coimbra , Coimbra , Portugal.
authors.forename: Marina
authors.initials: M
authors.lastname: Ribeiro
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|d CNC.IBILI, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: Ana Margarida
authors.initials: AM
authors.lastname: Abrantes
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|d CNC.IBILI, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|e CICS-UBI, Health Sciences Research Centre, University of Beira Interior , Covilhã , Portugal.
authors.forename: Ana Catarina
authors.initials: AC
authors.lastname: Mamede
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|d CNC.IBILI, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Laranjo
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: João Eduardo
authors.initials: JE
authors.lastname: Casalta-Lopes
authors.affiliation: b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|d CNC.IBILI, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|f Applied Molecular Biology and Hematology Group, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Gonçalves
authors.affiliation: b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|d CNC.IBILI, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|f Applied Molecular Biology and Hematology Group, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: Ana Bela
authors.initials: AB
authors.lastname: Sarmento-Ribeiro
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|g Surgical Department , Surgery A, CHUC , Coimbra , Portugal.
authors.forename: José Guilherme
authors.initials: JG
authors.lastname: Tralhão
authors.affiliation: a Biophysics and Biomathematics Institute, IBILI-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|b Center of Investigation on Environmental, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra , Coimbra , Portugal.|d CNC.IBILI, Faculty of Medicine, University of Coimbra , Coimbra , Portugal.
authors.forename: Maria Filomena
authors.initials: MF
authors.lastname: Botelho
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D051272:Glucose Transporter Type 1; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; C495677:SLC2A1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019788:Fluorodeoxyglucose F18; D009536:Niacinamide; D011794:Quercetin; D000077157:Sorafenib