title: Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport function.
abstract: OBJECTIVE
  Cediranib (recentin, AZD2171) is an oral small-molecule multiple receptor tyrosine kinases inhibitor. Here we investigate the ability of cediranib to reverse tumor multidrug resistance (MDR) due to overexpression of ABCB1 (P-glycoprotein) and ABCC1 (MRP1) transporters.
  
  
  METHODS
  KBv200,MCF-7/adr, C-A120 and their parental sensitive cell lines KB, MCF-7 and KB-3-1 were used for reversal study. The intracellular accumulations of doxorubicin and rhodamine 123 were determined by flow cytometry. The expressions levels of ABCB1 and ABCC1 were investigated by Western blot and RT-PCR analyses. ATPase activity assay were performed by Luminescence. The functions of ERK in MCF-7/adr were investigated by RNA interference.
  
  
  RESULTS
  Cediranib significantly enhanced the sensitivity of ABCB1 or ABCC1 substrates in MDR cells, with no effect found on sensitive cells. However, the expressions of these transporters were not affected and the reversal activity of cediranib was not related to the phosphorylation of AKT or ERK1/2. Further studies showed that cediranib inhibited ATPase activity of ABCB1 (P-glycoprotein) in a dose-dependent manner.
  
  
  CONCLUSIONS
  Cediranib reverses ABCB1- and ABCC1-mediated MDR by directly inhibiting their drug efflux function. These findings may be useful for cancer combinational therapy with cediranib in the clinic.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Li-Yang
authors.initials: LY
authors.lastname: Tao
authors.forename: Yong-Ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Chen
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Yan
authors.forename: Chun-Ling
authors.initials: CL
authors.lastname: Dai
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D006801:Humans; D007202:Indicators and Reagents; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123; D013778:Tetrazolium Salts; D013844:Thiazoles; D007211:Indoles
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D002352:Carrier Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051058:Oncogene Protein v-akt; D011799:Quinazolines; D020112:Rhodamine 123; D013778:Tetrazolium Salts; D013844:Thiazoles; C513055:ABCB1 protein, human; C022616:thiazolyl blue; C500926:cediranib; D007211:Indoles; C421109:multidrug resistance-associated protein 1