title: The effects of proteasome inhibitor bortezomib on a P-gp positive leukemia cell line K562/A02.
abstract: The aim of this study is to clarify the efficacy of proteasome inhibitor bortezomib to multidrug resistant (MDR) acute leukemia cells. We observed the effects of bortezomib on a P-glycoprotein (P-gp) positive leukemia line K562/A02. The results showed that bortezomib has significant effects on P-gp positive K562/A02 cells including cytotoxicity (48 h IC(50): 171.36 nM), induction of apoptosis (31.71 +/- 1.07% apoptotic cells after 24 h treatment at 100 nM), and inhibition of proteasome chymotrypsin-like activity (relative activity to untreated controls: 20.07 +/- 0.66% at 24 h with 10 nM bortezomib). These effects were lower than those observed in K562 cells (IC(50), percentage of apoptotic cells, relative chymotrypsin-like activity to untreated controls were 56.28 nM, 77.95 +/- 0.35%, 5.35 +/- 2.05% after the same treatments, respectively). No synergy between daunorubicin and bortezomib was shown in the killing of K562/A02 cells (synergistic ratios were <1). P-gp expression levels did not decrease in K562/A02 cells after bortezomib treatment. Pretreatment with bortezomib does not improve the intracellular anthracycline concentration in K562/A02 cells. Bortezomib shows a promising effect for the treatment of refractory/relapsed leukemia, but it does not improve the effect of anthracycline to MDR leukemia cells.
authors.affiliation: Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Lü
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: F
authors.initials: F
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D002918:Chymotrypsin