title: Hypomethylation agent decitabine restores drug sensitivity by depressing P-glycoprotein activity through MAPK signaling pathway.
abstract: The multidrug resistance (MDR) continues to be an obstacle in the treatment of both hematological and solid tumors. Hypomethylation agent, decitabine (5-Aza-dC), is an experimental agent in MDR therapy, while the mechanism is not very clear. In the present study, we demonstrated 5-Aza-dC may reverse MDR induced by P-glycoprotein (P-gp) coded by mdr1 gene in both hematologic K562/ADR cells and solid tumor MCF-7/ADR cells with time and dose-dependent manner. 5-Aza-dC significantly increased drug sensitivity in patients' leukemic cells which had higher expression of mdr1 gene. Both total protein and membrane P-gp expression were up-regulated with 5-Aza-dC treatment in K562/ADR and MCF-7/ADR cells. However, accumulation of adriamycin and rhodamine 123 were increased which suggested the depression of P-gp activity. Gene expression profiling was performed and activation of MAPK signaling pathway was identified as the most significant change affected by 5-Aza-dC. Inhibition of MAPK pathway could increase P-gp activity. Our data suggested that hypomethylation agent decitabine restores drug sensitivity in the P-gp-induced MDR phenotype by depressing of P-gp activity as drug pump partly through MAPK signaling pathway.
authors.affiliation: Department of Hematology, Shengjing Hospital, China Medical University, No. 39 Huaxiang Street, Shenyang, 110021, China.
authors.forename: Huihan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Urology, Shengjing Hospital, China Medical University, Shenyang, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology, Shengjing Hospital, China Medical University, No. 39 Huaxiang Street, Shenyang, 110021, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Liao
authors.affiliation: Department of Hematology, Shengjing Hospital, China Medical University, No. 39 Huaxiang Street, Shenyang, 110021, China. Liuzg@sj-hospital.org.
authors.forename: Zhuogang
authors.initials: Z
authors.lastname: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077209:Decitabine; D005260:Female; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D009363:Neoplasm Proteins; D000077209:Decitabine; D001374:Azacitidine
keywords: Hypomethylation; MAPK pathway; P-gp activity