Atiprimod blocks phosphorylation of JAK-STAT and inhibits proliferation of acute myeloid leukemia (AML) cells.
In studies of multiple myeloma cells, atiprimod was shown to block Stat3 activation and inhibited colony-forming cell proliferation. We hypothesized that atiprimod may also inhibit activation of intracellular signaling pathways in AML cells resulting in apoptosis and growth inhibition. We demonstrate that atiprimod inhibited clonogenic growth of AML cell lines and fresh AML marrow cells whereas it did not significantly affect growth of normal hematopoietic progenitors from marrow samples of healthy controls. Atiprimod decreased phosphorylation of Stat3 and Stat5, and protein levels of Jak2, whereas gene expression of Jak2 was not affected. Atiprimod further induced apoptosis by cleavage of caspase 3 and PARP. In summary, our data suggest that atiprimod has a significant antiproliferative and proapoptotic effect on AML cells. This effect may be facilitated by inhibition of the Jak-Stat signaling pathway. Further evaluation of atiprimod in clinical trials of AML should be considered.
Faderl
Stefan
S
Department of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030, USA. sfaderl@mdanderson.org
Ferrajoli
Alessandra
A
Harris
David
D
Van
Quin
Q
Kantarjian
Hagop M
HM
Estrov
Zeev
Z
D000208:Acute Disease; D001752:Blast Crisis / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000494:pharmacology
D017931:DNA Primers; D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D013141:Spiro Compounds; C099015:azaspirane; D053614:Janus Kinase 2