Differentiation of human promonocytic leukemia U-937 cells with DNA topoisomerase II inhibitors: induction of vimentin gene expression.
The administration of the DNA topoisomerase II inhibitors 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) (10(-7) M), VP-16 (2 x 10(-7) M), or novobiocin (1.5 x 10(-4) M) reduces the growth activity of human promonocytic leukemia U-937 cells, by arresting them preferentially at the G2 (m-AMSA and VP-16) or at the G1 and G2 (novobiocin) phases of the cell cycle. Under these conditions, m-AMSA and VP-16 induce the differentiation of the cells efficiently, as proved both by an increase in the production of reactive oxygen species and by the activation of the surface expression of CD11b and CD11c, two differentiation-specific antigens. Novobiocin also induces the expression of those differentiation markers, but to a lesser extent. Analyses by Northern blot indicate that the topoisomerase II inhibitors reduce the levels of c-myc and beta-actin mRNA and increase the levels of vimentin mRNA. The expression of vimentin is also stimulated at the protein level, as indicated by immunofluorescence assays. This represents one of the few known instances in which topoisomerase inhibitors stimulate gene expression in eukaryotic cells.
Rius
C
C
Centro de Investigaciones Biológicas, C.S.I.C., Madrid, Spain.
Zorrilla
A R
AR
Cabañas
C
C
Mata
F
F
Bernabeu
C
C
Aller
P
P
D000677:Amsacrine / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D009675:Novobiocin / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000235:genetics*
D000943:Antigens, Differentiation; D059005:Topoisomerase II Inhibitors; D014746:Vimentin; D000677:Amsacrine; D009675:Novobiocin; D005047:Etoposide; D010100:Oxygen