Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos.
Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos.
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DOI：
10.1158/1535-7163.mct-09-0198
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发表时间：
2009-09
影响因子：
5.7
通讯作者：
Rodeck U
中科院分区：
文献类型：
--
作者：
Daroczi B;Kari G;Ren Q;Dicker AP;Rodeck U
炎症反应是正常组织对电离辐射（IR）反应的主要组成部分，NF-κB活性的增加是炎症反应的重要介质。在这里，我们使用斑马鱼胚胎来评估已知靶向NF-κB的两种不同类别的药理学试剂改变脊椎动物生物体中的辐射毒性的能力。这些是蛋白酶体抑制剂，包括Lactacystin、MG 132和PS-341（Bortez/万珂），以及NF-κB活性的直接抑制剂，包括丙酮酸乙酯（EP）和合成三萜类化合物CDDO-TFEA（RTA 401）等。蛋白酶体抑制剂没有显著影响斑马鱼胚胎的辐射敏感性（MG 132，Lactacystin）或使斑马鱼胚胎对IR的致死效应更敏感（PS-341）。PS-341的放射增敏作用在p53表达或功能受损的鱼中降低，但与选择的p53靶基因的表达增强无关。相比之下，直接NF-κB抑制剂EP和CDDO-TFEA显著提高了致死辐射斑马鱼胚胎的总体存活率。此外，直接抑制NF-κB可减少中枢神经系统中辐射诱导的细胞凋亡，消除体轴发育中的畸变，恢复报告脂质通过胃肠道系统的代谢和分泌，并改善辐射损害的肾清除率。与氨磷汀相比，EP和CDDO-TFEA在暴露后1-2小时给药时不仅保护免受辐射毒性，而且减轻辐射毒性。最后，另外四种具有不同作用机制的IKK抑制剂同样提高了致死性辐照斑马鱼胚胎的总体存活率。总之，NF-κB活化的经典途径抑制剂可能有助于减轻患者的辐射毒性。
Inflammatory changes are a major component of the normal tissue response to ionizing radiation (IR) and increased NF-κB activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacological agents known to target NF-κB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors including Lactacystin, MG132 and PS-341 (Bortezomib/VELCADE) and direct inhibitors of NF-κB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401) among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, Lactacystin) or rendered zebrafish embryos more sensitive to lethal effects of IR (PS-341). Radiosensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-κB inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-κB inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system and improved renal clearance compromised by radiation. In contrast to Amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1–2 h post-exposure. Finally, four additional IKK inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-κB activation may be useful in alleviating radiation toxicity in patients.