title: Proteasome inhibitor bortezomib overcomes P-gp-mediated multidrug resistance in resistant leukemic cell lines.
abstract: BACKGROUND
  To study the effect of bortezomib alone or in combination with daunorubicin (DNR) on an mdr1 single-factor drug-resistant leukemia cell line K562/MDR1, a multifactor-resistant cell line K562/A02, a drug-sensitive cell line K562, and primary cells from acute myeloid leukemia patients.
  
  
  METHODS
  The cell lines were exposed to bortezomib, DNR, and bortezomib plus DNR, and cell proliferation, cell cycle, apoptosis rate, and expression of MDR1/BCL2 were analyzed.
  
  
  RESULTS
  Bortezomib potently inhibited growth and increased the apoptosis rate in the cell lines. In K562/MDR1 and K562/A02, the calcium channel blocker verapamil reduced the 50% inhibitory concentration and apoptosis rate of DNR, a P-gp protein substrate, but not of bortezomib. Bortezomib plus DNR had synergistic effect on antiproliferation (synergistic ratio > 1). Apoptosis was substantially more increased by the combination of two drugs than by bortezomib alone. Bortezomib arrested the cell cycles of three cell lines at the G2/M stage, decreased BCL2 mRNA expression, but did not affect MDR1 mRNA levels. The antiproliferative role of bortezomib was also confirmed in primary leukemia cells.
  
  
  CONCLUSIONS
  Bortezomib is a promising potential therapy for acute leukemia, especially mdr1 drug-resistant leukemia.
authors.affiliation: Department of Hematology and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: B
authors.initials: B
authors.lastname: Zheng
authors.forename: R
authors.initials: R
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Gong
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: Q
authors.initials: Q
authors.lastname: Shan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D003630:Daunorubicin