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.

Olean-12-Eno[2,3-c] [1,2,5]Oxadiazol-28-Oic Acid (OEOA) Induces G1 Cell Cycle Arrest and Differentiation in Human Leukemia Cell Lines

“…K562 cells can be differentiated into erythroid cells, which are marked by the increased expression of embryonic/fetal globin genes, such as ζ-, ε- , and γ-globin genes [24], [34]. It has also been suggested that K562 cells can be differentiated into megakaryocytic lineage with the expression of a surface marker, CD41b [35].…”

Induction of erythroid differentiation and increased globin mRNA production with furocoumarins and their photoproducts

“…4). It should be underlined that the level of induction reached in these experimental conditions is even higher than that exhibited by the most powerful inducer described [30].…”

“…The level of induction was found to be dose-dependent, all the analyzed globin mRNAs were clearly induced, the level of induction was dramatic for α-globin, ζ-globin and γ-globin mRNA sequences, but clearly evident also for ε-globin mRNA. When the experiment was repeated ( n  = 3) using the highest furocoumarin concentration reproducible results were observed, and if the results were compared to reference K562 cells treated with a control HbF inducer, this induction level was higher than the most effective K562 erythroid inducer available, 1-octylthymine [30]. In fact the induction of ζ-globin mRNA was 48.5-fold ± 8.5 for 4′,5′-DMP, 64.6-fold ± 8.2 for 4,6,4′-TMA and 37-fold ± 6.8 for 1-octylthymine (data not shown and Ref.…”

Consensus Predictive Model for Human K562 Cell Growth Inhibition through Enalos Cloud Platform

“…K562 cells are also commonly used for the screening of various inhibitors, including Bcr‐Abl kinase inhibitor candidates and antitumor compounds that induce cell differentiation . Differentiation treatment is an advanced strategy for neoplasia therapies and is based on the identification and use of pharmaceutical agents that act as differentiation promoters …”