In vitro effect on human leukemic K562 cells of co-administration of liposome-associated retinoids and cytosine arabinoside (ara-C)

Abstract

The administration of retinoids has been demonstrated to be of potential utility in the therapy of a wide spectrum of neoplastic pathologies due to the ability to induce differentiation in a large variety of primary tumor cells as well as in vitro cultured cell lines. Moreover, a number of compounds, including hemin, cytosine arabinoside, and 5-azacytidine are able to induce erythroid differentiation of the erythroleukemic cell line K562. In this paper we determined whether a combined treatment of K562 cells with suboptimal concentrations of cytosine arabinoside and retinoids containing liposomes lead to a full expression of differentiated functions. Liposomes were prepared by reverse phase evaporation technique followed by extrusion through polycarbonate filters. Cell growth kinetics studies and intracellular detection of hemoglobin by benzidine staining were performed. The results obtained showed that the combined treatment with liposomes containing retinoids and sub-optimal concentration of ara-C is an effective strategy to induce K562 cell differentiation, minimizing at the same time toxic effects. Control experiments aimed to determine possible selection of subpopulations of K562 cells suggest that the observed results are not related to toxicity and/or potential selection of induced cells. In conclusion, liposomally delivered retinoids could be proposed for differentiation therapy as an effective strategy in the treatment and management of malignancy. In addition, the finding that liposomally delivered retinoids increase the capacity of cytosine arabinoside to induce erythroid differentiation, could be of interest in studies aimed at the development of treatment able to reactivate fetal globin genes in beta-thalassemia patients.

A non‐apoptotic function of caspase‐3 in pharmacologically‐induced differentiation of K562 cells

“…In this clearly defined genetic background, pharmacologically‐induced differentiation has been studied extensively (Morceau et al. , 1996; Belhacène et al., 1998; Cortesi et al. , 1999; Bianchi et al.…”

“…For example, 12‐0‐ tetradecanoylphorbol‐13‐acetate (TPA) stimulates megakaryocytic development, while anthracyclines, haemin, hydroxyurea, GTP, cyclopentenyl cytosine (CPEC), cytosine arabinoside (Ara‐C), cisplatin, imatinib (STI571) and butyric acid have been shown to cause erythroid differentiation of K562 cells (Morceau et al. , 1996; Belhacène et al., 1998;Cortesi et al. , 1999; Bianchi et al.…”

“…In each case, differentiation of K562 cells appeared to be a common outcome when tested drugs were used at low non‐toxic concentrations (Morceau et al. , 1996; Cortesi et al. , 1999; Bianchi et al.…”

“…Only haemin, an iron-containing porphyrin, which is the prosthetic moiety for a broad range of proteins involved in oxygen delivery, is not employed in anticancer chemotherapy as a cytostatic drug, but is used in acute porphyria and in patients with thalassaemia intermedia (Nakamichi et al, 2005). In each case, differentiation of K562 cells appeared to be a common outcome when tested drugs were used at low non-toxic concentrations (Morceau et al, 1996;Cortesi et al, 1999;Bianchi et al, 2000;Park et al, 2001;Woessmann and Mivechi, 2001;Czyz et al, 2005;Di Pietro et al, 2007).…”

Development of K562 cell clones expressing β‐globin mRNA carrying the β039 thalassaemia mutation for the screening of correctors of stop‐codon mutations

“…Interestingly, especially for reaching the aims of the present study, K562 cells express the β -globin gene at very low levels both in their uninduced state as well as after erythroid differentiation stimulated by a variety of chemical inducers, such as cytosine arabinoside [24], mithramycin [25,26] and rapamycin [27,28]. …”