In vitro dual effect of arsenic trioxide on hemopoiesis: inhibition of erythropoiesis and stimulation of megakaryocytic maturation.
Although the arsenic compounds are now widely utilized in clinics in the treatment of various tumors, their effects on normal hematopoiesis do not seem to have been explored. In the present study, we provide evidence that arsenic trioxide (As(2)O(3)) exerts in vitro a potent inhibitory effect on normal erythropoiesis and a stimulatory action on megakaryocytic differentiation. The effect of As(2)O(3) on erythroid and megakaryocytic differentiation was evaluated on both erythroleukemic cell lines K562 and HEL and on normal hemopoietic progenitor cells (HPCs) induced to selective erythroid or megakaryocytic differentiation. The inhibitory effect of As(2)O(3) on erythropoiesis is related to: (a) the inhibition of Stat5 activation with consequent reduced expression of the target genes Bcl-X(L) and glycophorin-A; (b) the activation of an apoptotic mechanism that leads to the cleavage of the erythroid transcription factors Tal-1 and GATA-1, whose integrity is required for erythroid cell survival and differentiation; (c) the reduced expression of heat shock protein 70, required for GATA-1 integrity. The stimulatory effect of As(2)O(3) on normal megakaryocytopoiesis is seemingly related to upmodulation of GATA-2 expression and to stimulation of MAPK activity. These observations may have implications for the patients undergoing anti-leukemic treatment with this compound.
Saulle
Ernestina
E
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Riccioni
Roberta
R
Pelosi
Elvira
E
Stafness
Marit
M
Mariani
Gualtiero
G
De Tuglie
Giampiero
G
Peschle
Cesare
C
Testa
Ugo
U
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006021:Glycophorins / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis
D000970:Antineoplastic Agents; D001152:Arsenicals; C494811:BCL2L1 protein, human; D006021:Glycophorins; D010087:Oxides; D014157:Transcription Factors; D051020:bcl-X Protein; D020929:Mitogen-Activated Protein Kinase Kinases; D000077237:Arsenic Trioxide