JTE-607, a multiple cytokine production inhibitor, induces apoptosis accompanied by an increase in p21waf1/cip1 in acute myelogenous leukemia cells.
Proinflammatory cytokines and growth factors have been thought to play crucial roles in the pathology of acute myelogenous leukemia (AML) by supporting the proliferation and survival of AML cells in an autocrine and paracrine manner, although further elucidation is required. JTE-607 was originally identified as a multiple cytokine inhibitor that suppresses production of proinflammatory cytokines from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. Herein, we report that JTE-607 exhibits inhibitory activity on the growth of AML cell lines accompanying reduction of the proinflammatory cytokine and growth factor production. In in vitro studies, JTE-607 suppressed expression and production of cytokines, which are spontaneously up-regulated in AML cell lines. JTE-607 also abrogated proliferation of AML cells in a concentration range in which colony formation of normal bone marrow cells was not affected. The growth inhibition by JTE-607 was characterized by induction of cell-cycle arrest at the S-phase and apoptosis, accompanied by a decrease in c-Myc and increase in p21(waf1/cip1). In a leukemia model engrafted with U-937 cells, JTE-607 significantly prolonged survival in mice and reduced human cytokine mRNA levels in the bone marrow. These results suggest the usefulness of JTE-607 in therapeutic applications for patients with hypercytokinemia and aggressive AML cell proliferation.
Tajima
Nobuyuki
N
Biological and Pharmacological Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. nobuyuki.tajima@jt.com
Fukui
Kenji
K
Uesato
Naofumi
N
Maruhashi
Junji
J
Yoshida
Takayuki
T
Watanabe
Yoshihiro
Y
Tojo
Arinobu
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; C468268:JTE 607; D010879:Piperazines; D042461:Vascular Endothelial Growth Factor A; D010649:Phenylalanine