Sodium Channel Blockers as Inhibitors of Prostate Cancer

钠通道阻滞剂作为前列腺癌的抑制剂

基本信息

批准号：
6889277
负责人：
Milton L. Brown
金额：
$ 31.86万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Recently, the invasive and metastatic potential of prostate cancer was correlated with the expression of a voltage-gated sodium channel in human and rat prostate cancer (PCa) cell lines. A 260-kd protein, corresponding to a voltage-gated sodium channel, was identified in PC-3 and highly metastatic Mat-LyLu PCa cell lines. This sodium channel isotype was inhibited by tetrodotoxin (TTX) and identified as a voltage dependent channel. Further investigation into the relationship between human prostate expressed Na+ channel and the invasive phenotype found that TTX reduced the invasiveness of PC-3 cells by 31% (P = 0.02). Since metastatic prostate adenocarcinoma is the second most common cause of cancer-related deaths among men in North America, a large void in effective treatment regimens still exists. We hypothesize that sodium channel modulating agents will be effective in preventing or limiting PCa growth and/or metastasis. With this in mind, we propose to evaluate novel sodium channels blockers as inhibitors of LNCaP, C4-2, PC3, PC-3M and DU145 human PCa cell lines. In this new investigator proposal, we demonstrate using thymidine uptake, crystal violet growth assays, MTT, and soft agarose assays that our lead compounds inhibit androgen dependent and independent PCa cell lines. Preliminary data from our laboratory identified two classes of novel inhibitors that have potent cellular inhibitory effects at 40 micromolar when tested over 7 days of treatment. Furthermore, these analogues were more effective at inhibiting all PCa cell lines tested to date as compared to known sodium channel blocking agents like phenytoin and lidocaine. Altogether, this work lays the framework for the evaluation of these novel compounds in vivo. We are encouraged by these preliminary results and specifically aim to: 1) synthesize novel analogs of the active leads designed with systematic changes to evaluate, 2) evaluate the electrophysiological properties of the novel analogs for sodium channel activity, 3) evaluate the novel analogs for inhibition of human prostate cancer cell line (LNCaP, C4-2, PC3, PC-3M and Du-145) growth, tumorigenic and metastatic potential using in vitro model systems and 4) evaluate the novel active analogs for inhibition of human prostate cancer growth, tumorigenic and metastatic potential using in vivo model systems.

描述（由申请人提供）：最近，前列腺癌的侵袭性和转移潜力与人和大鼠前列腺癌（PCA）细胞系中电压门控通道的表达相关。在PC-3和高度转移性Mat-Lylu PCA细胞系中鉴定出对应于电压门控钠通道的260 kD蛋白。该钠通道同种型被四毒素（TTX）抑制，并鉴定为依赖电压通道。进一步研究人类前列腺表达的Na+通道和侵入性表型之间的关系发现，TTX将PC-3细胞的侵入性降低了31％（P = 0.02）。由于转移性前列腺腺癌是北美男性与癌症相关死亡的第二大最常见原因，因此仍然存在有效治疗方案中的大空隙。我们假设钠通道调节剂将有效预防或限制PCA生长和/或转移。考虑到这一点，我们建议评估新型的钠通道阻滞剂作为LNCAP，C4-2，PC3，PC-3M和DU145人PCA细胞系的抑制剂。在这项新的研究者建议中，我们证明了使用胸苷摄取，晶体紫罗兰色生长测定，MTT和软琼脂糖测定法表明，我们的铅化合物抑制了依赖雄激素和独立的PCA细胞系。来自我们实验室的初步数据确定了两类的新型抑制剂，这些抑制剂在7天的治疗中测试时具有40微摩尔的有效细胞抑制作用。此外，与已知的钠通道阻断剂（如苯妥英和利多卡因）相比，这些类似物在抑制迄今为止测试的所有PCA细胞系方面更有效。总的来说，这项工作为评估这些新颖化合物在体内的评估奠定了框架。 We are encouraged by these preliminary results and specifically aim to: 1) synthesize novel analogs of the active leads designed with systematic changes to evaluate, 2) evaluate the electrophysiological properties of the novel analogs for sodium channel activity, 3) evaluate the novel analogs for inhibition of human prostate cancer cell line (LNCaP, C4-2, PC3, PC-3M and Du-145) growth, tumorigenic and使用体外模型系统的转移潜力和4）评估新型的活性类似物，以抑制人类前列腺癌的生长，肿瘤和转移性潜能，并使用体内模型系统中的转移性潜力。