Induction of erythroid differentiation and modulation of gene expression by tiazofurin in K-562 leukemia cells.

Abstract

Cancer can be viewed as a disorder generating from an uncoupling of gene expression that controls cellular proliferation and differentiation. Therefore, much attention has been paid to cancer cell lines that can be induced to differentiate after in vitro exposure to chemical or chemotherapeutic agents (for reviews, see refs. 1-3). The K-562 human leukemia cell line provides a useful system for studying human erythroid differentiation because it expresses markers of erythroid lineages, such as hemoglobin.Of the variety of chemotherapeutic agents used in cancer treatment, some can induce cell differentiation (4). In our previous studies we used drugs directed against key enzymes of purine and pyrimidine metabolism (5-7). Activities of target enzymes of these drugs were those that were tightly linked with in vivo and in vitro proliferative activity (5,8,9). The activity of IMP dehydrogenase (IMP:NAD' oxidoreductase; EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, markedly increased in various types of cancer cells; therefore, this enzyme was suggested as a sensitive target for anticancer chemotherapy (5, 10). Tiazofurin (2-i-D-ribofuranosyl-4-thiazolecarboxamide;NSC-286193) potently inhibits the proliferation ofa variety of experimental and human neoplasms and is now in phase I and II clinical trial (11, 12

Acylphosphatase possesses nucleoside triphosphatase and nucleoside diphosphatase activities

“…Although these authors have suggested a different mechanism, the observed block of this Ras-p21 biological function could be due to the acylphosphatase-induced GTP hydrolysis in this cell type. Furthermore, other authors have demonstrated that K562 cell differentiation by tiazofurin is accompanied by the early decrease of cellular GTP [38]. Similar considerations can be made for the possible changes in cellular ATP levels caused by the ATPase activity of acylphosphatase during apoptosis.…”

Role of Ras/ERK-dependent pathway in the erythroid differentiation of K562 cells

“…The expression of this fusion gene product is associated with an increase in tyrosine phosphorylated proteins that leads to activation of intracellular signaling pathways such as Ras and PI3-kinase ( P u i l et Skorski et al, 1997). It has been shown that a specific reduction of Bcr-Abl PTK activity with human a b l antisense oligonucleotide and CGP57148 induces erythroid differentiation of K562 cells Carroll et al, 1997), and downregulation of Hras, K-ras and N-ras expression is associated with the erythroid differentiation induced by Ara-C and tiazofurin ( D e l g a d o et Olah et al, 1988;We b e r et al, 1991). However, modulation of signaling pathway that is required to induce erythroid differentiation is still not clearly understood.…”

“…Decrease in H-r a s, K-r a s and N-r a s expression (H-r a s was affected more dramatically than K-r a s and N-r a s) was found in the erythroid differentiated K562 cells after exposure to Ara-C (Delgado et al, 1992). Ti a z o f u r i n causes down-regulation of c-Ki-r a s gene (Olah et al, 1988;Weber et al, 1991) In addition, decrease in c-myc gene expression was observed in the K562 cells treated with Ara-C (Bianchi Scarra et al, 1986;To n i n i et al, 1987).…”

Induction of apoptosis in IL-3–dependent hematopoietic cell lines by guanine nucleotide depletion

“…14, 15 The IMPDH inhibitor tiazofurin also induced downregulation of the expression of c-Ki-ras, c-Ha-ras, and G-proteinmediated transmembrane signaling. 14,16,17 Inhibition of IMPDH activity results in the differentiation of a number of cell lines, 18,19 whereas the induction of apoptosis is limited to only a few cell types. 20,21 Mycophenolic acid (MPA), a highly specific, uncompetitive inhibitor of IMPDH, was tested against the panel of 60 cell lines at the National Cancer Institute (http://dtp.nci.nih.gov) and was found to have growth inhibitory effects against most neoplastic cell types, with leukemias being the most sensitive.…”