Acquisition of doxorubicin resistance in human leukemia HL-60 cells is reproducibly associated with 7q21 chromosomal anomalies.
Tumor cell resistance to doxorubicin (DOX) is usually associated with the overexpression of P-glycoprotein (PGP) in model systems. We have characterized the karyotypic changes in two sublines of HL-60 cells which differ in the induction of differentiation by retinoic acid. The parental sublines, designated HL-60A/S and HL-60Y/S, were selected in increasing concentrations of 0.025-0.1 micrograms/mL DOX. Monosomy 8 in HL-60Y/S was the only karyotypic difference prior to DOX exposure. Both sublines acquired 7q+ markers upon exposure to DOX. In HL-60Y/S, and add(7)(q21) replaced one homologue at 0.025 micrograms/mL DOX, and an add(7)(q32) appeared which replaced the other normal 7 at 0.05 micrograms/mL DOX. The HL-60A/S cells acquired an add(7)(q21) at 0.025 micrograms/mL DOX. The 7q+ abnormalities involved breakpoints in the midregion of 7q. The overexpression of phosphorylated PGP in immunoprecipitates with C-219 antibody was identified in both sublines of DOX-resistant HL-60 cells with 7q+ abnormalities, and this is consistent with the location of mdr-1 sequences to 7q21-21.1. Also, analysis of RNA from parental-sensitive and DOX-resistant sublines by reverse transcriptase-polymerase chain reaction revealed: a) comparable expression of multidrug resistance related protein (MPR) in sensitive and resistant sublines; and b) overexpression of mdr-1 only in the DOX-resistant sublines. Thus, the selection of DOX resistance in two sublines of HL-60 cells which differ in their response to retinoic acid-induced myeloid differentiation is reproducibly associated with overexpression of mdr-1 versus MRP.
Ganapathi
R
R
Department of Cancer Biology, Research Institute, Cleveland Clinic Foundation, Ohio 44195, USA.
Hoeltge
G
G
Casey
G
G
Grabowski
D
D
Neelon
R
R
Ford
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D007621:Karyotyping; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D014212:Tretinoin / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D014212:Tretinoin; D004317:Doxorubicin