Design, synthesis, and evaluation of novel sodium channel blockers as inhibitors of human prostate cancer

Sodium (Na+) channels are large membrane-spanning proteins involved in the propagation and maintenance of cellular excitability and are able to switch between different states to enable selective permeability for Na+ ions. Voltagegated sodium channels (VGSCs) are widely expressed in excitable tissues such as those composed of neuronal, neuroendocrine, skeletal, and cardiac cells.; It is well established that VGSCs play a crucial role in “excitable” (nerve and muscle) cells. However, there is also increasing evidence that VGSCs also occur in other “non-excitable” cell types such as lymphocytes, osteoblasts, endothelia, and fibroblasts. It is known that cancer cells express ion channels, that differential expression of ion channels may influence metastatic potential, and that the expression of ion channels can be controlled by mitogens and oncogenes. At this point it is not known whether the expression of ion channels in cells of different metastatic ability is related to the cells' proliferative activity. However, recent studies have shown that the expression of VGSCs is related to the metastatic potential of several prostate cancer cell lines.; The role of VGSCs and the localization of these cells in the prostate and prostate cancer have not been thoroughly investigated. The recent discovery of sodium channel expression in human prostate cancer cells led to the investigatation of the potential use of neuronal sodium channel blockers as inhibitors of prostate cancer cells. Initial studies led to the discovery of two classes of sodium channel blockers that were effective inhibitors of prostate cancer cell proliferation. Both hydroxyamides and hydantoins were shown to inhibit the androgen-independent (Al) prostate cancer cell line PC-3 in vitro . Electrophysiology showed all compounds functionally block brain type II voltage gated sodium channels (Na_v 1.2) expressed in Xenopus oocytes. Long-term growth assays in PC-3 cells showed remarkable inhibition of cell growth with cells growing to a maximum of 30% of controls. Further, these analogues demonstrated only marginal impact on cell viability over the treatment interval. Altogether, this data indicates that these novel sodium channel blockers inhibit prostate cancer cell proliferation in a non-toxic manner and may be viable agents in the treatment of human prostate cancer.