Development of human leukemia U-937 cell sublines resistant to doxorubicin: induction of differentiation and altered sensitivities to topoisomerase-directed drugs.
Cell sublines resistant to doxorubicin (DOX) were developed from the human leukemia cell line, U-937/WT, exposed to stepwise DOX increases. In contrast to U-937/WT cells, the DOX-resistant U-937/RD cells have longer doubling time; are more differentiated along the monocytic lineage as determined by the presence of morphological features and mRNA coding for the monocyte colony-stimulating factor-1 receptor; synthesize the apoptosis-associated Bax protein; are less sensitive to apoptosis-inducing topoisomerase II-directed drugs, apparently because of increased synthesis of P-glycoprotein; and are practically non-tumorigenic when xenografted in nude mice. However, U-937/WT and U-937/RD cells exhibit similar sensitivity to the apoptosis-inducing drug 9-nitrocamptothecin. These findings suggest that several mechanisms are involved in the development of DOX-resistance in U-937 cells, and further, 9-nitrocamptothecin can overcome resistance to DOX. These findings may have clinical implications.
Pantazis
P
P
Stehlin Foundation for Cancer Research, St. Joseph Hospital, Houston, TX, USA.
Dejesus
A
A
Early
J
J
Rodriguez
R
R
Chatterjee
D
D
Han
Z
Z
Wyche
J
J
Giovanella
B
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D016186:Receptor, Macrophage Colony-Stimulating Factor; D004250:DNA Topoisomerases, Type II