title: Effect of BIBF 1120 on reversal of ABCB1-mediated multidrug resistance.
abstract: BACKGROUND
  The overexpression of ATP-binding cassette (ABC) transporters is one of the main causes of multi-drug resistance (MDR) which represents a major obstacle to the success of cancer chemotherapy. In this study, we examined the effect of BIBF 1120, an inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs) tyrosine kinases, on the reversal of multidrug resistance in vitro.
  
  
  METHODS
  The doxorubicin and rhodamine 123 retention assay was performed by flowcytometry. Western blot were employed to identify ABCB1 expression level and the effect of BIBF 1120 on the blockade of Akt and ERK1/2 phosphorylation. The expression of mdr1 mRNA was determined by RT-PCR analysis. The ATPase activity of ABCB1 was investigated using Pgp-Glo™ assay systems.
  
  
  RESULTS
  BIBF 1120 significantly enhanced the cytotoxicity of doxorubicin and paclitaxel and increased the accumulation of ABCB1 substrates in ABCB1-overexpressing cancer cells, whereas it had no effect on the parental cells. On the other hand, BIBF 1120 did not alter the cytotoxicity of non-ABCB1 substrates and was unable to reverse ABCC1 or ABCG2-mediated MDR. Furthermore, BIBF 1120 inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. However, no detectable alteration on the expression level of mdr1 mRNA or ABCB1 protein was identified in ABCB1-overexpressing cancer cells by different treatments of BIBF 1120. Interestly, total and phosphorylated forms of AKT and ERK1/2 were not inhibited by BIBF 1120 at the reversal concentrations.
  
  
  CONCLUSIONS
  Our results suggest that BIBF 1120 is capable of overcoming ABCB1-mediated drug resistance by inhibiting ABCB1 function, which may have clinical significance for BIBF 1120 combinational treatment of certain resistant cancers.
authors.affiliation: Department of General Surgery, Chen Xing Hai Hospital, Guangdong Medical College, Zhongshan 528415, China.
authors.forename: Qing-feng
authors.initials: QF
authors.lastname: Xiang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Xiao-dong
authors.initials: XD
authors.lastname: Su
authors.forename: Yong-ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Li-sheng
authors.initials: LS
authors.lastname: Zheng
authors.forename: Yan-jun
authors.initials: YJ
authors.lastname: Mi
authors.forename: Wei-qiang
authors.initials: WQ
authors.lastname: Chen
authors.forename: Li-wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007211:Indoles; D020112:Rhodamine 123; D004317:Doxorubicin; D014700:Verapamil; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C530716:nintedanib