JTE-607, a multiple cytokine production inhibitor, induces apoptosis accompanied by an increase in p21waf1/cip1 in acute myelogenous leukemia cells
JTE-607, a multiple cytokine production inhibitor, induces apoptosis accompanied by an increase in p21waf1/cip1 in acute myelogenous leukemia cells
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DOI：
10.1111/j.1349-7006.2009.01446.x
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发表时间：
2010-03-01
期刊：
影响因子：
5.7
通讯作者：
Tojo, Arinobu
中科院分区：
文献类型：
--
作者：
Tajima, Nobuyuki;Fukui, Kenji;Tojo, Arinobu
促炎细胞因子和生长因子被认为在急性髓性白血病（AML）的病理中起着至关重要的作用，通过自分泌和旁分泌的方式支持AML细胞的增殖和存活，尽管需要进一步的阐明。JTE-607最初被认为是一种多种细胞因子抑制剂，可抑制脂多糖（LPS）刺激的外周血单个核细胞产生促炎细胞因子。在此，我们报道JTE-607对AML细胞系的生长具有抑制活性，同时减少促炎细胞因子和生长因子的产生。在体外研究中，JTE-607抑制细胞因子的表达和产生，这些细胞因子在AML细胞系中自发上调。在不影响正常骨髓细胞集落形成的浓度范围内，JTE-607也能抑制AML细胞的增殖。JTE-607抑制生长的特点是诱导细胞周期阻滞于s期和凋亡，同时伴有c-Myc的减少和p21（waf1/cip1）的增加。在移植U-937细胞的白血病模型中，JTE-607显著延长小鼠的存活时间，降低骨髓中人细胞因子mRNA水平。这些结果表明JTE-607在高细胞素血症和侵袭性AML细胞增殖患者的治疗应用中的有效性。（癌症科学2010；101:774-781）
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. (Cancer Sci 2010; 101: 774-781)