• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>BMC Medical Genomics >Cidofovir selectivity is based on the different response of normal and cancer cells to DNA damage
【24h】

Cidofovir selectivity is based on the different response of normal and cancer cells to DNA damage

机译：西多福韦的选择性基于正常细胞和癌细胞对DNA损伤的不同反应

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Background Cidofovir (CDV) proved efficacious in treatment of human papillomaviruses (HPVs) hyperplasias. Antiproliferative effects of CDV have been associated with apoptosis induction, S-phase accumulation, and increased levels of tumor suppressor proteins. However, the molecular mechanisms for the selectivity and antitumor activity of CDV against HPV-transformed cells remain unexplained. Methods We evaluated CDV drug metabolism and incorporation into cellular DNA, in addition to whole genome gene expression profiling by means of microarrays in two HPV+ cervical carcinoma cells, HPV- immortalized keratinocytes, and normal keratinocytes. Results Determination of the metabolism and drug incorporation of CDV into genomic DNA demonstrated a higher rate of drug incorporation in HPV+ tumor cells and immortalized keratinocytes compared to normal keratinocytes. Gene expression profiling clearly showed distinct and specific drug effects in the cell types investigated. Although an effect on inflammatory response was seen in all cell types, different pathways were identified in normal keratinocytes compared to immortalized keratinocytes and HPV+ tumor cells. Notably, Rho GTPase pathways, LXR/RXR pathways, and acute phase response signaling were exclusively activated in immortalized cells. CDV exposed normal keratinocytes displayed activated cell cycle regulation upon DNA damage signaling to allow DNA repair via homologous recombination, resulting in genomic stability and survival. Although CDV induced cell cycle arrest in HPV- immortalized cells, DNA repair was not activated in these cells. In contrast, HPV+ cells lacked cell cycle regulation, leading to genomic instability and eventually apoptosis. Conclusions Taken together, our data provide novel insights into the mechanism of action of CDV and its selectivity for HPV-transformed cells. The proposed mechanism suggests that this selectivity is based on the inability of HPV+ cells to respond to DNA damage, rather than on a direct anti-HPV effect. Since cell cycle control is deregulated by the viral oncoproteins E6 and E7 in HPV+ cells, these cells are more susceptible to DNA damage than normal keratinocytes. Our findings underline the therapeutic potential of CDV for HPV-associated malignancies as well as other neoplasias.
机译：背景西多福韦（CDV）被证明可有效治疗人乳头瘤病毒（HPV）增生。 CDV的抗增殖作用与细胞凋亡诱导，S期积累和肿瘤抑制蛋白水平升高有关。但是，CDV对HPV转化细胞的选择性和抗肿瘤活性的分子机制仍无法解释。方法除了通过微阵列技术在两个HPV + 子宫颈癌细胞HPV -永生化角质形成细胞中进行全基因组基因表达谱分析外，我们还评估了CDV药物的代谢和掺入细胞DNA中的能力。和正常的角质形成细胞。结果CDV的代谢和药物掺入基因组DNA的测定表明，与正常角质形成细胞相比，HPV + 肿瘤细胞和永生化角质形成细胞中药物掺入的比率更高。基因表达谱清楚地显示了在所研究的细胞类型中独特和特定的药物作用。尽管在所有细胞类型中均观察到对炎症反应的影响，但与永生化角质形成细胞和HPV + 肿瘤细胞相比，在正常角质形成细胞中发现了不同的途径。值得注意的是，Rho GTPase途径，LXR / RXR途径和急性期反应信号在永生化细胞中被专门激活。暴露于CDV的正常角质形成细胞在DNA损伤信号转导后表现出活化的细胞周期调控，从而允许DNA通过同源重组修复，从而导致基因组稳定性和存活。尽管CDV诱导了HPV -永生化细胞的细胞周期停滞，但这些细胞中的DNA修复并未激活。相比之下，HPV + 细胞缺乏细胞周期调控，导致基因组不稳定，并最终导致细胞凋亡。结论总之，我们的数据为CDV的作用机理及其对HPV转化细胞的选择性提供了新颖的见解。拟议中的机制表明这种选择性是基于HPV + 细胞不能对DNA损伤做出反应，而不是基于直接的抗HPV效应。由于HPV + 细胞中的病毒癌蛋白E6和E7可以调节细胞周期控制，因此这些细胞比正常的角质形成细胞更容易受到DNA损伤。我们的发现强调了CDV在与HPV相关的恶性肿瘤以及其他瘤形成中的治疗潜力。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号