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Camptothecin Induces Differentiation and Stimulates the Expression of Differentiation-related Genes in U-937 Human Promonocytic Leukemia Cells¹

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Velázquez 144, 28006-Madrid, Spain [P. A., C. R., A. Z., T. B., C. B.], and Departamento de Bioquimica y Biologia Molecular I, Facultad de Ciencias Quimicas [F. M.] and Departamento de Bioquimica y Biologia Molecular III [C. C.], Facultad de Medicina, Universidad Complutense, Madrid, Spain

We have studied the effect of the DNA topoisomerase I inhibitor camptothecin on growth, differentiation, and gene expression in U-937 human promonocytic leukemia cells. At a concentration of 20 nM, camptothecin caused significant DNA strand breakage and decreased the growth activity by accumulating cells preferentially at the G₂ phase of the cycle. The growth arrest occurred concomitantly with an increase in cell size. Under those conditions, camptothecin induced differentiation, as demonstrated by (a) the capacity of the cells to generate reactive oxygen species, (b) the increase in the surface expression of the leukocyte integrins CD11b/CD18 and CD11c/CD18, (c) the increase in the cellular content of the intermediate filament protein vimentin, and (d) the decrease in the surface expression of the transferrin receptor. Camptothecin also induced the expression of differentiation markers in other human myeloid cells, namely, the promonocytic THP-1 and the myelomonocytic HL-60 cell lines. Northern blot assays revealed that camptothecin stimulated the expression of CD11b, CD11c, and vimentin at the mRNA level. Moreover, the drug increased the transcription rate of the vimentin gene, as shown by "run-on" transcription assays.

¹ Supported by Dirección General de Investigación Cientifica y Técnica (Spain) grants PB87-0351 and PB87-0286 and by Fondo de Investigaciones Sanitarias de la Seguridad Social (Spain) grant 87/1693.

² To whom requests for reprints should be addressed.

³ Recipient of a predoctoral from the Plan de Formación de Personal Investigador (Spain).

Received 4/16/91. Accepted 12/13/91.

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