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.