Characterization of a human myeloid leukemia cell line highly resistant to taxol.
Taxol-resistant sublines of HL-60 myeloid leukemia cells (HL-60/TAX100 and HL-60/TAX1000) have been isolated in vitro by subculturing in progressively higher concentrations of taxol. HL-60/TAX100 and HL-60/TAX1000 cells are capable of continuous growth in the presence of 0.1 microM and 1.0 microM taxol, respectively, and the IC50 (50% growth inhibitory dose) values for taxol for the two sublines are 0.34 and 2.44 microM as compared to 3.1 nM for the parent HL-60 cells. HL-60/TAX100 and HL-60/TAX1000 cells display a variable degree of cross-resistance to taxotere, vincristine and doxorubicin, but are sensitive to the antimetabolite Ara-C. Both HL-60/TAX100 and HL-60/TAX1000 cells over-express MDR-1 m-RNA and the membrane efflux multidrug transporter P-glycoprotein (PGP), as determined by Western blot and immunofluorescence labeling with anti-PGP antibodies. Consequently, exposure of the taxol-resistant cells to [3H]taxol or daunomycin results in the accumulation of significantly lower levels of the two drugs. Co-treatment with cyclosporine (0.5 microgram/ml) or verapamil (10 microM) partially overcomes taxol resistance in HL-60/TAX1000 cells. Following treatment with clinically relevant concentration of taxol (1.0 microM for 24 h), HL-60 but not HL-60/TAX1000 cells display intracellular microtubular bundling, markedly enhanced accumulation of the cells in G2/M phase of cell-cycle and internucleosomal DNA fragmentation associated with apoptosis which is independent of bcl-2 gene expression. These taxol-resistant myeloid leukemia cells may serve as in vitro experimental models for examinating strategies which may have potential applicability for overcoming taxol resistance.
Bhalla
K
K
Department of Medicine, Medical University of South Carolina, Charleston.
Huang
Y
Y
Tang
C
C
Self
S
S
Ray
S
S
Mahoney
M E
ME
Ponnathpur
V
V
Tourkina
E
E
Ibrado
A M
AM
Bullock
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D008562:Membrane Glycoproteins; D016572:Cyclosporine; D014700:Verapamil; D017239:Paclitaxel; D003630:Daunorubicin