• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Cytotoxic effects of novel small molecules on PC3 prostate cancer cells.
【24h】

Cytotoxic effects of novel small molecules on PC3 prostate cancer cells.

机译：新型小分子对PC3前列腺癌细胞的细胞毒性作用。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Prostate cancer (PCa) is the most common cancer among men and is the second leading cause of cancer-related deaths in males in the United States and Europe. PCa is more common in African-American than Caucasian-American men, potentially because African-American men have a higher expression of androgen receptors. Early treatments include deprivation of androgen and removal of prostate tissues. However, these treatments may be rendered ineffective as the disease progresses to become androgen-independent (the castrate refractory stage) and as the tumor metastasizes. Finding additional and more effective treatments for castrate refractory PCa is highly desirable. Our lab has previously identified peptides that stabilize Holliday junctions (HJs) formed during DNA recombination reactions by inhibiting their resolution. HJs are intermediates in homologous recombination repair (HRR) pathway and cancer cells depend more on HRR than normal cells as they have uncontrolled replication and proliferation. Our most potent peptide, wrwycr, is active as a homodimer. In order to increase the potential of developing chemotherapeutic agents targeting DNA repair, we identified non-peptide small molecule surrogates from over 20 different chemical scaffolds; two types of scaffolds yielded small molecules (1609-3, 1609-10, 1795-3 and 1795-10) that shared some properties with the peptides, including interactions with HJs. Results of cell viability and cytotoxicity assays have shown that all of the 1609 and 1795 compounds caused cell death in PC3 cells, and that one of the molecules reduces total DNA synthesis, but not total RNA or protein synthesis. Small molecule-induced cell death is lethal and independent of p53-induced apoptosis. In addition, small molecules induce double-stranded DNA breaks, as evident from the activation of DNA damage sensors, gammaH2AX and p53-binding protein 1 (53BP1). As expected, the downstream signaling checkpoint proteins, Chk1 and Chk2 are activated in consequence. However, no cell cycle arrest was observed. However, contrary to our hypothesis that the small molecules may interfere with double strand break repair, there was no synergy between compound 1795-10 and ionizing radiation.
机译：前列腺癌（PCa）是男性中最常见的癌症，并且是美国和欧洲男性与癌症相关的死亡的第二大主要原因。 PCa在非裔美国人中比白种美国人更普遍，这可能是因为非裔美国人男性具有更高的雄激素受体表达。早期治疗包括剥夺雄激素和去除前列腺组织。但是，随着疾病发展为变得不依赖雄激素（去势难治期）以及肿瘤转移，这些治疗方法可能无效。寻找去势难治性PCa的其他更有效的治疗方法是非常需要的。我们的实验室之前已经鉴定出了通过抑制DNA重组来稳定DNA重组反应中形成的霍利迪连接（HJs）的肽。 HJ是同源重组修复（HRR）途径的中间体，癌细胞比正常细胞更依赖HRR，因为它们具有不受控制的复制和增殖。我们最有效的肽wrwycr具有同二聚体的活性。为了增加开发针对DNA修复的化学治疗剂的潜力，我们从20多种不同的化学支架中鉴定了非肽小分子替代物；两种类型的支架产生的小分子（1609-3、1609-10、1795-3和1795-10）与这些肽具有一些特性，包括与HJ的相互作用。细胞活力和细胞毒性测定的结果表明，所有1609和1795化合物都导致PC3细胞死亡，并且其中一种分子减少了总DNA合成，但没有降低总RNA或蛋白质合成。小分子诱导的细胞死亡是致死性的，与p53诱导的细胞凋亡无关。此外，从DNA损伤传感器，gammaH2AX和p53结合蛋白1（53BP1）的激活可以明显看出，小分子诱导了双链DNA断裂。正如预期的那样，下游信号转导检查点蛋白Chk1和Chk2被激活。但是，没有观察到细胞周期停滞。但是，与我们的小分子可能干扰双链断裂修复的假设相反，化合物1795-10与电离辐射之间没有协同作用。

著录项

  • 作者

    Udompholkul, Parima.;

  • 作者单位

    San Diego State University.;

  • 授予单位 San Diego State University.;
  • 学科 Molecular biology.;Oncology.;Neurosciences.
  • 学位 M.S.
  • 年度 2016
  • 页码 49 p.
  • 总页数 49
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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