Redox Modulation of Prostate Cancer

描述（由申请人提供）：核因子κ β (NF-kB)是一种氧化还原敏感转录因子，已被确定为促凋亡和促生存蛋白编码基因的调节因子。研究表明，激素非依赖性前列腺癌具有高水平的NF-kB组成，癌症治疗剂激活NF-kB可以减弱这些药物的活性，导致癌细胞死亡。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NF-kB家族选定成员及其促生存的NF-kB靶基因产物，包括初级抗氧化酶、锰超氧化物歧化酶和抗凋亡蛋白BclXL。我们还发现辐射诱导NF-kB以双波模式激活。我们假设具有高水平组成NF-kB的肿瘤细胞对NF-kB介导的细胞保护通路的抑制敏感，并且调节该通路可以改善侵袭性前列腺癌的放射反应。亲代PC-3及其NF-kB突变衍生细胞系将被用作雄激素非依赖型前列腺癌细胞的模型。亲本LNCaP及其衍生物将作为雄激素依赖性前列腺癌细胞的模型。我们将在体外和体内研究PC-3衍生和LNCaP衍生的前列腺癌细胞系。5周龄雄性胸腺裸鼠将通过前列腺原位植入作为人类前列腺癌细胞的宿主。Specific aim 1旨在鉴定NF-kB家族中在侵袭性前列腺癌细胞的高内在放射耐药中起重要作用的特定成员。特异性目标2旨在测试NF-kB选择性调制或基于氧化还原的干预可用于增强辐射敏感性的概念。特异性靶3旨在验证特异性靶2在实验性治疗环境中的结果。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。这些信息可以作为选择性方法发展的基本原理，最终可能转化为显著的临床效益。

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.