title: C(5) modified uracil derivatives showing antiproliferative and erythroid differentiation inducing activities on human chronic myelogenous leukemia K562 cells.
abstract: The K562 cell line has been proposed as a useful experimental system to identify anti-tumor compounds acting by inducing terminal erythroid differentiation. K562 cells exhibit a low proportion of hemoglobin-synthesizing cells under standard cell growth conditions, but are able to undergo terminal erythroid differentiation when treated with a variety of anti-tumor compounds. In this paper we report a screening study on a set of different modified C(5) uracil derivatives for the evaluation of their antiproliferative effect in connection with erythroid differentiation pathways, and for defining a new class of drug candidates for the treatment of chronic myelogenous leukemia. Activity of the derivatives tested can be classified in two effect: an antiproliferative effect linked to a high level of erythroid differentiation activity and an antiproliferative effect without activation of gamma globin genes The highest antiproliferative effect and erythroid induction was shown by compound 9, a thymine derivative bearing a n-octyl chain on nitrogen N(1), whereas thymine did not show any effect, suggesting the importance of the linear alkyl chain in position N(1). To our knowledge this compound should be considered among the most efficient inducers of erythroid differentiation of K562 cells. This work is the starting point for the quest of more effective and specific drugs for the induction of terminal erythroid differentiation, for leading new insights in the treatment of neoplastic diseases with molecules acting by inducing differentiation rather than by simply exerting cytotoxic effects.
authors.affiliation: BioPharmaNet, Department of Biochemistry and Molecular Biology, Molecular Biology Division, University of Ferrara, Via Luigi Borsari, 46-44100 Ferrara, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Brognara
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lampronti
authors.forename: Giulia
authors.initials: G
authors.lastname: Breveglieri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Accetta
authors.forename: Roberto
authors.initials: R
authors.lastname: Corradini
authors.forename: Alex
authors.initials: A
authors.lastname: Manicardi
authors.forename: Monica
authors.initials: M
authors.lastname: Borgatti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Canella
authors.forename: Chiara
authors.initials: C
authors.lastname: Multineddu
authors.forename: Rosangela
authors.initials: R
authors.lastname: Marchelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014498:Uracil / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D055544:beta-Globins / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D055544:beta-Globins; D055545:gamma-Globins; D014498:Uracil