• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Drug Target Insights >17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells
【24h】

17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells

机译：17AAG治疗加速阿霉素诱导的细胞衰老：Hsp90干扰肿瘤细胞的强制衰老。

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

摘要

Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an alternate strategy. Here, we demonstrate that inhibiting Hsp90 with 17AAG sensitizes human neuroblastoma to DNA damage response mediated cellular senescence. Among individual and combination drug treatments, 17AAG pre-treatment followed by doxorubicin treatment exhibited senescence-like characteristics such as increased nucleus to cytoplasm ratio, cell cycle arrest, SA-β-gal staining and the perpetual increase in SAHF. Doxorubicin induced senescence signaling was mediated by p53-p21 CIP/WAF-1 and was accelerated in the absence of functional Hsp90. Sustained p16 and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence. Despite increases in [(ROS)i] and [(Ca2+INK4a)i], a concomitant increase in cellular antioxidant defense system suggested oxidation independent senescence activation. Sustained activation of survival (Akt) and proliferative (ERK1/2) kinases fosters robustness of cells. Invigorating senescent cells with growth factor or snooping with mTOR or PI3 kinase inhibitors compromised cell survival but not senescence. Intriguingly, senescence-associated secretory factors from the senescence cells manifested established senescence in neuroblastoma, which offers clinical advantage to our approach. Our study discusses tumor selective functions of Hsp90 and discusses irrefutable strategies of Hsp90 inhibition in anticancer treatments.
机译：Hsp90分子伴侣已被确定为对抗癌症的有吸引力的药理靶标。但是，一些转移性肿瘤要么对Hsp90抑制反应无效，要么显示出恢复，因此需要不可逆的治疗策略。响应于这种强制衰老，已经提出了另一种策略。在这里，我们证明用17AAG抑制Hsp90使人神经母细胞瘤对DNA损伤反应介导的细胞衰老敏感。在单独和联合药物治疗中，先进行17AAG预处理再进行阿霉素治疗，具有衰老样特征，如细胞核比增加，细胞周期停滞，SA-β-gal染色和SAHF永久增加。阿霉素诱导的衰老信号转导由p53-p21 CIP / WAF-1介导，并在不存在功能性Hsp90的情况下被加速。与未受影响的端粒酶激活相关的持续的p16和H3K4me3表达废除了复制性衰老和评估的应激诱导的衰老。尽管[（ROS）i]和[（Ca2 + INK4a）i]有所增加，但细胞抗氧化剂防御系统的同时增加表明，氧化独立的衰老激活。存活（Akt）和增殖（ERK1 / 2）激酶的持续激活可增强细胞的健壮性。使用生长因子激发衰老细胞或使用mTOR或PI3激酶抑制剂进行窥探会损害细胞存活率，但不会损害衰老。有趣的是，来自衰老细胞的衰老相关分泌因子在神经母细胞瘤中显示出已确立的衰老，这为我们的方法提供了临床优势。我们的研究讨论了Hsp90的肿瘤选择性功能，并讨论了在抗癌治疗中抑制Hsp90的不可辩驳的策略。

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