Previous work suggested that functional voltage-gated Na+ channels (VGSCs) are expressed specifically in strongly metastatic cells of rat and human prostate cancer (PCa), thereby raising the possibility that VGSC activity could be involved in cellular behavior(s) related to the metastatic cascade. In the present study, the possible role of VGSCs in the lateral motility of rat PCa cells was investigated in vitro by testing the effect of modulators that either block or enhance VGSC activity. Two rat PCa cell lines of markedly different metastatic ability were used in a comparative approach: the strongly metastatic MAT-LyLu and the weakly metastatic AT-2 cell line, only the former being known to express functional VGSCs. Using both electrophysiological recording and a motility assay, the effects of two VGSC blockers (tetrodotoxin and phenytoin) and four potential openers (veratridine, aconitine, ATX 11, and brevetoxin) were monitored on (a) Na+ channel activity and (b) cell motility over 48 h. Tetrodotoxin (at 1 muM) and phenytoin (at 50 muM) both decreased the motility index of the MAT-LyLu cell line by 47 and 11 %, respectively. Veratridine (at 20 muM) and brevetoxin (at 10 nM) had no effect on the motility of either cell line, whilst aconitine (at 100 muM) and ATX 11 (at 25 pM) significantly increased the motility of the MAT-LyLu cell line by 15 and 9%, respectively. importantly, at the concentrations used, none of these drugs had effects on the proliferation or viability of either cell line. The results, taken together, would suggest strongly that functional VGSC expression enhances cellular motility of PCa cells. The relevance of these findings to the metastatic process in PCa is discussed. (C) 2003 Wiley-Liss, Inc.