title: α1-Adrenergic drugs modulate differentiation and cell death of human erythroleukemia cells through non adrenergic mechanism.
abstract: Preliminary data showed that α1-adrenergic antagonists induce apoptosis and a switch towards megakaryocytic differentiation in human erythroleukemia cells. To test the hypothesis whether survival and differentiation of erythroleukemia cells are under control of α1-adrenergic signalling, we examined α1-adrenoceptor expression of erythroleukemia cells and compared the in vitro effects of α-adrenergic antagonists with those of agonists. We discovered that α1-adrenergic agonists suppress both erythroid differentiation and growth of erythroleukemia cells concomitant with lipofuscin accumulation, autophagy and necrotic cell death. α1-adrenergic agonists also inhibit the in vitro growth of physiologic hematopoietic progenitors obtained from umbilical cord blood with high selectivity for the erythroid lineage. Interestingly, the observed effects could not be related to α1-adrenoceptors, even though agonists and antagonists displayed opposing effects regarding cellular growth and differentiation of erythroleukemia cells. Our data suggest that the effects of α1-adrenergic drugs are related to a non-adrenoceptor binding site, controlling the fate of erythroid progenitor cells towards differentiation and cell death. Since the observed effects are not mediated through adrenoceptors, the physiologic relevance of our data remains unclear, so far. Nevertheless, the identification of the still unknown binding site(s) might disclose new insights into regulation of erythroid differentiation and cell death.
authors.affiliation: Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, Heinrichstrasse 31A, Graz, Austria. robert.fuchs@medunigraz.at
authors.forename: Robert
authors.initials: R
authors.lastname: Fuchs
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schraml
authors.forename: Gerd
authors.initials: G
authors.lastname: Leitinger
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Stelzer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Allard
authors.forename: Helga Susanne
authors.initials: HS
authors.lastname: Haas
authors.forename: Konrad
authors.initials: K
authors.lastname: Schauenstein
authors.forename: Anton
authors.initials: A
authors.lastname: Sadjak
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006021:Glycophorins / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology; D009278:Naphazoline / Q000494:pharmacology; D009336:Necrosis / Q000139:chemically induced; D010075:Oxathiins / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D006021:Glycophorins; D006454:Hemoglobins; D010075:Oxathiins; D018340:Receptors, Adrenergic, alpha-1; D006427:Hemin; C050877:benoxathian; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D053148:Caspase 3; D009278:Naphazoline; D011224:Prazosin