Erythroid differentiation and growth inhibition of K562 cells by 2',5'-dideoxyadenosine: synergism with interferon-alpha.
We found that 2',5'-dideoxyadenosine (DDA), a P-site specific adenylate cyclase inhibitor, inhibited the growth of K562 cells and caused them to become benzidine positive. The continuous exposure of cells to DDA was needed to recruit cells for growth inhibition and differentiation. Fetal calf or human sera were also necessary for DDA to induce differentiation. DDA at a concentration of 1.5 mM with serum induced 98% of the cells to produce hemoglobin and inhibited their growth to 15% of that of the control. An increase of epsilon-globin mRNA and a decrease of c-myc and c-myb mRNA occurred only during differentiation in the presence of fetal calf serum (FCS). An incubation with DDA and interferon-alpha (IFN-alpha) or hemin synergistically induced more benzidine-positive cells than in the presence of DDA alone, although IFN-alpha did not trigger differentiation by itself. The erythroid differentiation and growth inhibition were, however, not related to a decreased intracellular cyclic AMP (cAMP) concentration induced by DDA. The simultaneous incubation with dibutyryl cyclic AMP (dbc-AMP) and DDA enhanced the effects of DDA. Adenine, a possible metabolite of DDA digestion by purine nucleoside phosphorylase (PNP), also induced erythroid differentiation in K562 cells. However, it did not act synergistically with IFN-alpha.
Ogawa
K
K
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Tashima
M
M
Takeda
Y
Y
Sawai
H
H
Toi
T
T
Sawada
H
H
Maruyama
Y
Y
Okuma
M
M
D000225:Adenine / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005914:Globins / Q000235:genetics; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D011519:Proto-Oncogenes; D014407:Tumor Cells, Cultured
D000067956:Adenylyl Cyclase Inhibitors; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D016898:Interferon-alpha; D016048:Dideoxyadenosine; D005914:Globins; C021008:2',5'-dideoxyadenosine; D000225:Adenine