title: Reversal of multidrug resistance by 4-chloro-N-(3-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)phenyl)benzamide through the reversible inhibition of P-glycoprotein.
abstract: Overexpression of P-glycoprotein (P-gp) is one of the major obstacles to successful cancer chemotherapy. In this study, we examined the ability of 4-chloro-N-(3-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)phenyl)benzamide (C-4) to reverse multidrug resistance (MDR) in P-gp expressing KBV20C cells. Treatment of KBV20C cells with C-4 led to a dramatic increase in paclitaxel- or vincristine-induced cytotoxicity without any cytotoxicity by itself. In parallel, C-4 treatment caused an increase in apoptotic cell death by paclitaxel or vincristine. Furthermore, C-4 treatment significantly increases in intracellular accumulation of fluorescent P-gp substrate rhodamine 123, indicating that C-4 treatment leads to reversal of the MDR phenotype resulting from an increased accumulation of anticancer drugs by inhibiting drug efflux function of P-gp. This notion is further supported by the observation that C-4 treatment potentiates paclitaxel-induced G(2)/M arrest of the cell cycle. In addition, the drug efflux function of P-gp was reversibly inhibited by C-4 treatment, while the expression level of P-gp was not affected. Collectively, our results describe the potential of C-4 to reverse the P-gp-mediated MDR phenotype through reversible inhibition of P-gp function, which may make it an attractive new agent for the chemosensitization of cancer cells.
authors.affiliation: College of Medicine, Kwandong University, Gangneung 210-701, Republic of Korea. yksnbk@kwandong.ac.kr
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Song
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Seo
authors.forename: Dong-Won
authors.initials: DW
authors.lastname: Kang
authors.forename: Hoi Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
authors.forename: Chan Mug
authors.initials: CM
authors.lastname: Ahn
authors.forename: Seokjoon
authors.initials: S
authors.lastname: Lee
authors.forename: Su-Nam
authors.initials: SN
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000009:adverse effects* / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides / Q000633:toxicity*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005434:Flow Cytometry; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: C518652:4-chloro-N-(3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)phenyl)benzamide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D006139:Guaiacol