title: Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1.
abstract: OBJECTIVE
  A prerequisite for geldanamycin (GA, NSC122750) to targeting heat shock protein 90 and inhibiting tumor growth is sufficient intracellular drug accumulation. We hypothesized that membrane transporters on tumor cells determine at least in part the response to GA analogues.
  
  
  METHODS
  To facilitate a systematic study of chemosensitivity across a group of GA analogues with similar chemical structures, we correlated mRNA expression profiles of most known transporters with growth inhibitory potencies of compounds in 60 tumor cell lines (NCI-60). We subsequently validated the gene-drug correlations using cytotoxicity and transport assays.
  
  
  RESULTS
  Geldanamycin analogues displayed a range of negative correlations coefficients with ABCB1 (MDR1, or P-glycoprotein) expression. Suppressing ABCB1 in multidrug resistant cells (NCI/ADR-RES and K562/DOX) and ABCB1-transfected cells (BC19) increased sensitivity to GA analogues, as expected for substrates. Moreover, ABCB1-mediated efflux of daunorubicin in K562/DOX cells could be blocked markedly by GA analogues in a dose-dependent fashion. The IC(50) values (half-maximum inhibition of daunorubicin efflux) were 5.5, 7.3 and 12 muM for macbecin II (NSC330500), 17-AAG (NSC330507) and GA, respectively.
  
  
  CONCLUSIONS
  These observations demonstrate that GA analogues are substrates as well as inhibitors of ABCB1, suggesting that drug interactions between GA analogues and other agents that are ABCB1 substrates may occur via ABCB1 in normal or tumor cells.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA. yhuang@westernu.edu
authors: Ying
authors: Y
authors: Huang
authors: Paul E
authors: PE
authors: Blower
authors: Ruqing
authors: R
authors: Liu
authors: Zunyan
authors: Z
authors: Dai
authors: Anh-Nhan
authors: AN
authors: Pham
authors: Hojin
authors: H
authors: Moon
authors: Jialong
authors: J
authors: Fang
authors: Wolfgang
authors: W
authors: Sadée
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C001277:geldanamycin