Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate -: a novel nonpeptide IL-6 receptor antagonist
Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate -: a novel nonpeptide IL-6 receptor antagonist
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DOI：
10.1016/j.bbrc.2004.08.196
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发表时间：
2004-10-22
影响因子：
3.1
通讯作者：
Hayashi, M
中科院分区：
文献类型：
--
作者：
Enomoto, A;Rho, MC;Hayashi, M
在筛选新型IL-6抑制剂的同时，我们合成了20 S，21-环氧-脂蟾毒配基-3-乙酸酯（ERBA）。ERBA剂量依赖性地抑制IL-6诱导的细胞生长，IC 50值为5.3 μ M，并导致IL-6的剂量-反应曲线的平行双移。数据分析得出的pA 2为5.83，斜率为0.99。ERBA不影响IL-2、IL-3和GCSF依赖的细胞生长，也不影响肿瘤坏死因子α诱导的生长抑制，ERBA也不影响IL-11、白血病抑制因子和1 α，25-二羟维生素D-3诱导的破骨细胞形成。受体测定显示ERBA剂量依赖性地抑制IL-6与IL-6受体（IL-6 R）的结合。此外，当用IL-6刺激时，ERBA处理的细胞的Western印迹中IL-6 R位置不存在条带：ERBA通过阻断IL-6与IL-6 R的结合来抑制IL-6活性。在结肠26诱导的癌症恶病质的实验模型中，ERBA显著抑制体重减轻。ERBA是一种具有IL-6受体拮抗剂活性的特异性小分子。(C)2004年由Elsevier Inc.出版
While screening for novel IL-6 inhibitors, we synthesized 20S, 21-epoxy-resibufogenin-3-acetate (ERBA). ERBA dose-dependently suppressed IL-6-induced cell growth with an IC50 value of 5.3 muM and caused a parallel rightward shift of dose-response curves to IL-6. Analysis of data yields a pA2 of 5.83 and a slope of 0.99. ERBA did not affect IL-2-, IL-3-, and GCSF-dependent cell growth, or tumor necrosis factor alpha-induced growth suppression, nor did ERBA affect osteoclast formation induced by IL-11, leukemia inhibitory factor, and 1alpha,25-dihydroxyvitamin D-3. Receptor assay showed that ERBA dose-dependently suppressed IL-6 binding to IL-6 receptor (IL-6R). Furthermore, no band existing at the position of IL-6R in Western blots of ERBA-treated cells when stimulated with IL-6:ERBA suppresses IL-6 activity by blocking the binding of IL-6 to IL-6R. In an experimental model of colon 26-induced cancer cachexia, ERBA markedly inhibited body weight loss. ERBA is a specific small molecule with IL-6R-antagonist activity. (C) 2004 Published by Elsevier Inc.