Redox Modulation of Prostate Cancer

描述（由申请人提供）：核因子κ β（NF-κ B）是一种氧化还原敏感性转录因子，被公认为编码促凋亡和促存活蛋白的基因的调节因子。已经表明，非依赖性前列腺癌具有高组成性水平的NF-kB，并且癌症治疗剂对NF-kB的活化可以减弱这些药剂的活性以引起癌细胞死亡。该项目的目标是深入了解NF-kB介导的导致内在辐射抗性的机制，并确定可用于改善前列腺癌治疗的新方法。我们的初步数据表明，雄激素非依赖性前列腺癌具有高水平的选定成员的NF-κ B家族及其促生存NF-κ B靶基因产物，包括主要的抗氧化酶，锰超氧化物歧化酶，和抗凋亡蛋白，Bcl-XL。我们还发现，辐射诱导激活NF-κ B的两波模式。我们假设，具有高水平的组成性NF-κ B的肿瘤细胞将对NF-κ B介导的细胞保护途径的抑制敏感，并且该途径的调节可以改善侵袭性前列腺癌的放射反应。亲本PC-3及其NF-kB突变体衍生的细胞系将用作雄激素非依赖性前列腺癌细胞的模型。亲本LNCaP及其相应的衍生物将用作雄激素依赖性前列腺癌细胞的模型。将在体外和体内研究充分表征的PC-3衍生的以及LNCaP衍生的前列腺癌细胞系。将5周龄雄性无胸腺裸鼠用作人前列腺癌细胞的宿主，通过原位植入前列腺。具体目标1旨在鉴定在侵袭性前列腺癌细胞的高内在放射抗性中起重要作用的NF-κ B家族的特定成员。具体目标2旨在测试选择性调节NF-κ B或基于氧化还原的干预可用于增强辐射敏感性的概念。具体目标3旨在在实验治疗环境中验证具体目标2的结果。这项研究的完成将增强我们对NF-kB家族成员参与细胞存活的机制的理解。这一信息可以作为选择性方法的发展的基本原理，最终可能转化为显着的临床效益。

DESCRIPTION (provided by applicant): The nuclear factor kappa beta (NF-kB), a redox-sensitive transcription factor, is well established as a regulator of genes coding for both proapoptosis and prosurvival proteins. It has been shown that hormone-independent prostate cancer has a high constitutive level of NF-kB and activation of NF-kB by cancer therapeutic agents can blunt the activity of these agents to cause cancer cell death. The goal of this project is to gain insight into an NF-kB mediated mechanism leading to intrinsic radiation resistance and to identify novel approaches that can be used to improve the treatment of prostate cancer. Our initial data demonstrate that androgen-independent prostate cancer has high levels of selected members of the NF-kB family and its prosurvival NF-kB target gene products including the primary antioxidant enzyme, manganese superoxide dismutase, and the antiapoptotic protein, BclXL. We also found that radiation induced activation of NF-kB in a two-wave pattern. We hypothesize that tumor cells with high levels of constitutive NF-kB will be sensitive to inhibition of the NF-kB mediated cytoprotective pathway and modulation of this pathway can improve the radiation response of aggressive prostate cancer. Parental PC-3 and its NF-kB mutant derived cell lines will be used as models for androgen-independent prostate cancer cells. Parental LNCaP and its corresponding derivatives will be used as models for androgen-dependent prostate cancer cells. Well characterized PC-3 derived as well as LNCaP derived prostate cancer cell lines will be studied in vitro and in vivo. Five-weeks-old male athymic nude mice will be used as hosts of human prostate cancer cells by orthotopic implantation in the prostate glands. Specific aim 1 is designed to identify specific members of the NF-kB family that play an important role in high intrinsic radioresistance of aggressive prostate cancer cells. Specific aim 2 is designed to test the concept that selective modulation of NF-kB or redox-based intervention can be used to enhance radiation sensitivity. Specific aim 3 is designed to validate the results from Specific aim 2 in an experimental therapeutic setting. Accomplishment of this study will enhance our understanding of the mechanisms by which members of the NF-kB family participate in cell survival. This information can serve as a rationale for the development of selective approaches that might eventually translate into significant clinical benefit.