title: Histone deacetylase inhibitor apicidin-mediated drug resistance: involvement of P-glycoprotein.
abstract: Multidrug resistance (MDR), which is a significant impediment to the success of cancer chemotherapy, is attributable to the overexpression of membrane transport proteins, such as P-glycoprotein (P-gp), resulting in an increased drug efflux. In this study, we show that the histone deacetylase (HDAC) inhibitor apicidin leads to resistance of HeLa cells to paclitaxel through the induction of P-gp expression. Furthermore, apicidin dramatically increases the release of a fluorescent P-gp substrate, rhodamine 123, from cells. In parallel, apicidin resistance to the apoptotic potential of paclitaxel is associated with induction of P-gp expression in HeLa cells, as evidenced by specific inhibition of P-gp function using either the pharmacological inhibitor verapamil or RNA silencing. We also demonstrate the contribution of apicidin-induced functional P-gp expression to drug resistance using KB cells. Failure of P-gp induction by apicidin does not reverse paclitaxel-induced cytotoxicity in the cells. Although HDAC inhibitors are widely appreciated as a new class of anti-tumor agent, our findings clearly demonstrate that apicidin treatment may lead to P-gp-mediated resistance to other anti-tumor agents, suggesting a need for careful design of clinical applications using HDAC inhibitors.
authors.affiliation: Department of Pharmacology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea.
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
authors.forename: Nam Hyun
authors.initials: NH
authors.lastname: Kim
authors.forename: Jee Won
authors.initials: JW
authors.lastname: Hwang
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Song
authors.forename: Yeon-Suk
authors.initials: YS
authors.lastname: Park
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Seo
authors.forename: Hoi Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.forename: Su-Nam
authors.initials: SN
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000502:physiology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D020112:Rhodamine 123; D017239:Paclitaxel