The effect of topoisomerase inhibitors on the expression of differentiation markers and cell cycle progression in human K-562 leukemia cells.
Treatment of human K-562-J leukemia cells for 1 h with the topoisomerase II-reactive drugs VP-16, VM-26, or mAMSA resulted in a dose-dependent inhibition of proliferation and in an increase in the percentage of cells staining positive for hemoglobin, a marker of erythroid differentiation. Staining for hemoglobin of up to about 60% of the cells was observed at 20 microM VP-16, 1 microM VM-26, and 8 microM mAMSA. Such treatment also caused a G2/M arrest in the cell cycle. Incubation of the cells with radiolabeled VP-16 indicated that the induced erythroid differentiation was not due to continuous cell exposure to a residual amount of the drug. VP-16-induced erythroid differentiation was also not affected by DNA, RNA, or protein synthesis inhibitors. Differentiation induction and the G2/M arrest evoked by VP-16, VM-26, and mAMSA were, however, reduced in the presence of novobiocin. Our results indicate that topo-reactive drugs that cause G2/M arrest in the K-562-J cell cycle can induce in these cells erythroid differentiation after a short and irreversible interaction with their target molecule(s).
Constantinou
A
A
Biological and Medical Research Division, Argonne National Laboratory, Argonne, Illinois 60436-4833.
Grdina
D
D
Kiguchi
K
K
Huberman
E
E
D000677:Amsacrine / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D003513:Cycloheximide / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006454:Hemoglobins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008543:Melanins / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009675:Novobiocin / Q000494:pharmacology; D013713:Teniposide / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D003839:Deoxyadenosines; D006454:Hemoglobins; D008543:Melanins; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D009675:Novobiocin; D016590:Aphidicolin; D005047:Etoposide; D013713:Teniposide; D003513:Cycloheximide; C058120:cordycepin