title: HDAC inhibitors downregulate MRP2 expression in multidrug resistant cancer cells: implication for chemosensitization.
abstract: Although histone deacetylase (HDAC) inhibitors are emerging as a promising class of cancer chemotherapeutic agents, their effects on multidrug resistance (MDR) are poorly understood. In this study, we investigated whether HDAC inhibitors overcome MDR phenotype. HDAC inhibitors suppress the growth of both MDR positive cancer cells KBV20C and its parental cells KB with similar potencies. In parallel, histone acetylation and p21WAF1 expression by the HDAC inhibitors were similarly increased in both cell types, indicating that these HDAC inhibitors are poor substrates of ABC drug transporters and effective in MDR cancer cells. In addition, multidrug resistance protein 2 (MRP2) expression is selectively attenuated by HDAC inhibitors, especially SAHA and TSA, in KBV20C cells, whereas MDR1 and BCRP expressions are not affected. This downregulation of MRP2 contributes to increase in paclitaxel-induced G2/M arrest and apoptosis, which might be due to intracellular accumulation of paclitaxel. Collectively, our data provide a molecular rationale for the application of HDAC inhibitors to overcome MDR in cancer cells.
authors.affiliation: Department of Pharmacology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.forename: Su-Nam
authors.initials: SN
authors.lastname: Kim
authors.forename: Yeon-Suk
authors.initials: YS
authors.lastname: Park
authors.forename: Nam Hyun
authors.initials: NH
authors.lastname: Kim
authors.forename: Jeung Whan
authors.initials: JW
authors.lastname: Han
authors.forename: Hoi Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D000077337:Vorinostat; C000715087:ABCC2 protein, human