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首页> 外文学位 >Investigation of the intracellular signal transduction mechanisms that mediate the anticancer effects of gamma-tocotrienol in the neoplastic mouse +SA mammary epithelial cells.
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Investigation of the intracellular signal transduction mechanisms that mediate the anticancer effects of gamma-tocotrienol in the neoplastic mouse +SA mammary epithelial cells.

机译：介导γ-生育三烯酚在肿瘤小鼠+ SA乳腺上皮细胞中的抗癌作用的细胞内信号转导机制的研究。

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摘要

Treatment of tocotrienols in the highly malignant and metastatic +SA mouse mammary epithelial cells inhibits their growth and induces apoptosis in a time and a dose dependent manner. These results are observed at doses that have little or no effect on the proliferation and the viability of the normal mammary epithelial cells, and therefore, weigh therapeutic significance, and support the investigation of tocotrienols as potential adjuvant therapy in the prevention and the treatment of metastatic breast cancer. Studies were conducted to identify and investigate intracellular signal transduction mechanisms that are involved in the gamma-tocotrienol mediated anticancer effects in the +SA cells. Treatment with the growth inhibitory dose of gamma-tocotrienol resulted in a large decrease in the phosphorylated levels of Akt and suggested that the antiproliferative effects of gamma-tocotrienol in the +SA cells are associated with the suppression of the EGF (ErbB) induced PI3K/PDK-1/Akt mitogenic signaling. Studies that were conducted to determine the molecular target of inhibition by gamma-tocotrienol demonstrated no direct inhibitory effect of gamma-tocotrienol on any component along the PI3K/PDK-1/Akt signaling, suggesting that the inhibitory effects of gamma-tocotrienol were initiated upstream of the signaling cascade. Therefore, additional studies were conducted to determine the effects of gamma-tocotrienol on the ErbB receptor activation and results obtained therein demonstrated that although gamma-tocotrienol treatment had little or no effect on ErbB1 or ErbB2 receptor tyrosine phosphorylation, the same treatment caused a progressive decrease in the ErbB3 tyrosine phosphorylation, a prerequisite for the formation of the EGF receptor dimerization and activation of PI3K. Further, studies that were conducted to investigate the role played by the cell cycle regulators in the gamma-tocotrienol induced anticancer effects in the +SA cells demonstrated that both the gamma-tocotrienol mediated growth inhibition and the apoptosis of the +SA cells were associated with a large decrease in the levels and activity of cyclin D1 and cyclin-dependent kinase 4, which are the important regulators of the G1/S cell cycle checkpoint. Taken together, the studies conducted in the dissertation project have investigated and identified specific intracellular signal transduction mechanisms that underlie the gamma-tocotrienol mediated anticancer effects in the +SA mouse mammary epithelial cells.
机译：在高度恶性和转移性+ SA小鼠乳腺上皮细胞中治疗生育三烯酚会抑制其生长并以时间和剂量依赖性方式诱导凋亡。在对正常乳腺上皮细胞的增殖和活力几乎没有影响或没有影响的剂量下观察到这些结果，因此权衡了治疗意义，并支持研究生育三烯酚作为预防和治疗转移性的潜在辅助疗法乳腺癌。进行了研究以鉴定和研究与+ SA细胞中γ-生育三烯酚介导的抗癌作用有关的细胞内信号转导机制。用生长抑制剂量的γ-生育三烯酚处理可导致Akt的磷酸化水平大大降低，这表明γ-生育三烯酚在+ SA细胞中的抗增殖作用与EGF（ErbB）诱导的PI3K /的抑制有关PDK-1 / Akt有丝分裂信号传导。确定γ-生育三烯酚抑制分子靶标的研究表明，γ-生育三烯酚对PI3K / PDK-1 / Akt信号传导的任何成分均无直接抑制作用，表明γ-生育三烯酚的抑制作用始于上游信令级联。因此，进行了其他研究以确定γ-生育三烯酚对ErbB受体活化的影响，并且其中获得的结果表明，尽管γ-生育三烯酚处理对ErbB1或ErbB2受体酪氨酸磷酸化影响很小或没有影响，但相同的处理导致逐渐减少在ErbB3酪氨酸磷酸化中，EGF受体二聚化和PI3K活化的前提条件。此外，进行了研究以研究细胞周期调节剂在+ SA细胞中由γ-生育三烯酚诱导的抗癌作用中的作用，这些研究表明，γ-生育三烯酚介导的生长抑制和+ SA细胞的凋亡均与细胞周期蛋白D1和细胞周期蛋白依赖性激酶4的水平和活性大大降低，它们是G1 / S细胞周期检查点的重要调节剂。综上所述，在本研究项目中进行的研究已经调查并确定了特定的细胞内信号转导机制，这些机制是+ SA小鼠乳腺上皮细胞中γ-生育三烯酚介导的抗癌作用的基础。

著录项

  • 作者

    Samant, Ganesh Vinayak.;

  • 作者单位

    University of Louisiana at Monroe.;

  • 授予单位 University of Louisiana at Monroe.;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 77 p.
  • 总页数 77
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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