title: Dasatinib reverses the multidrug resistance of breast cancer MCF-7 cells to doxorubicin by downregulating P-gp expression via inhibiting the activation of ERK signaling pathway.
abstract: Multidrug resistance (MDR) is one of the major obstacles to the efficiency of cancer chemotherapy, which often results from the overexpression of drug efflux transporters such as P-glycoprotein (P-gp). In the present study, we determined the effect of dasatinib which was approved for imatinib resistant chronic myelogenous leukemia (CML) and (Ph(+)) acute lymphoblastic leukemia (ALL) treatment on P-gp-mediated MDR. Our results showed that dasatinib significantly increased the sensitivity of P-gp-overexpressing MCF-7/Adr cells to doxorubicin in MTT assays; thus lead to an enhanced cytotoxicity of doxorubicin in MCF-7/Adr cells. Additionally, dasatinib increased the intracellular accumulation, inhibited the efflux of doxorubicin in MCF-7/Adr cells, and significantly enhanced doxorubicin-induced apoptosis in MCF-7/Adr cells. Further studies showed that dasatinib altered the expression levels of mRNA, protein levels of P-gp, and the phosphorylation of signal-regulated kinase (ERK) both in time-dependent (before 24 h) and dose-dependent manners at concentrations that produced MDR reversals. In conclusion, dasatinib reverses P-gp-mediated MDR by downregulating P-gp expression, which may be partly attributed to the inhibition of ERK pathway. Dasatinib may play an important role in circumventing MDR when combined with other conventional antineoplastic drugs.
authors.affiliation: a Department of Clinical Pharmacology; College of Pharmacy ; Dalian Medical University ; Dalian , China.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Sun
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Yang
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013844:Thiazoles; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D000069439:Dasatinib
keywords: DOX, doxorubicin; ERK pathway; ERKextracellular signal-regulated kinase; MDR, multidrug resistance; P-ERK, phosphorylated extracellular signal–regulated kinase; P-glycoprotein; P-gp, P-glycoprotein; dasatinib; doxorubicin; multidrug resistance