Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Free Radic Biol Med. 2011 Dec 15;51(12):2249-58. doi: 10.1016/j.freeradbiomed.2011.09.029. Epub 2011 Oct 1.
We investigated the efficacy and mechanism of dimethylaminoparthenolide (DMAPT), an NF-κB inhibitor, to sensitize human lung cancer cells to X-ray killing in vitro and in vivo. We tested whether DMAPT increased the effectiveness of single and fractionated X-ray treatment through inhibition of NF-κB and/or DNA double-strand break (DSB) repair. Treatment with DMAPT decreased plating efficiency, inhibited constitutive and radiation-induced NF-κB binding activity, and enhanced radiation-induced cell killing by dose modification factors of 1.8 and 1.4 in vitro. X-ray fractionation demonstrated that DMAPT inhibited split-dose recovery/repair, and neutral DNA comet assays confirmed that DMAPT altered the fast and slow components of X-ray-induced DNA DSB repair. Knockdown of the NF-κB family member p65 by siRNA increased radiation sensitivity and completely inhibited split-dose recovery in a manner very similar to DMAPT treatment. The data suggest a link between inhibition of NF-κB and inhibition of DSB repair by DMAPT that leads to enhancement of X-ray-induced cell killing in vitro in non-small-cell lung cancer cells. Studies of A549 tumor xenografts in nude mice demonstrated that DMAPT enhanced X-ray-induced tumor growth delay in vivo.
我们研究了 NF-κB 抑制剂二甲氨基丙基噻吨酮（DMAPT）在体外和体内增强人肺癌细胞对 X 射线杀伤敏感性的疗效和机制。我们通过抑制 NF-κB 和/或 DNA 双链断裂（DSB）修复，测试了 DMAPT 是否能提高单次和分割 X 射线治疗的效果。DMAPT 处理降低了接种效率，抑制了组成性和辐射诱导的 NF-κB 结合活性，并在体外通过剂量修饰因子分别为 1.8 和 1.4 增强了辐射诱导的细胞杀伤。X 射线分割显示 DMAPT 抑制分割剂量恢复/修复，中性 DNA 彗星试验证实 DMAPT 改变了 X 射线诱导的 DNA DSB 修复的快速和慢速成分。siRNA 敲低 NF-κB 家族成员 p65 增加了辐射敏感性，并以与 DMAPT 处理非常相似的方式完全抑制了分割剂量恢复。数据表明，DMAPT 通过抑制 NF-κB 和 DSB 修复之间存在联系，从而增强了体外非小细胞肺癌细胞中 X 射线诱导的细胞杀伤。裸鼠 A549 肿瘤异种移植的研究表明，DMAPT 增强了体内 X 射线诱导的肿瘤生长延迟。
