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.
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