Effects of voltage-gated ion channel modulators on rat prostatic cancer cell proliferation: comparison of strongly and weakly metastatic cell lines.
BACKGROUND
The strongly metastatic MAT-LyLu and the weakly metastatic AT-2 rat prostatic cancer cell lines have been shown to express voltage-gated ion channels differentially. In the present study, the possible contribution of voltage-gated ion channel activity to the proliferation of these cell lines was investigated, in a comparative approach.


METHODS
Several voltage-gated ion channel modulators were tested for their effects on proliferation over 54 hr, using an in vitro assay. The modes of action of the chemicals were monitored by electrophysiological (patch-clamp) recording.


RESULTS
The voltage-gated K(+) channel blockers 4-aminopyridine (4-AP; 2 mM), margatoxin (5 nM), charybdotoxin (4.5 nM), and verapamil (50 microM) inhibited the K(+) channels of both cell lines by between 38-65% and reduced the proliferation of the AT-2 cell line, in a dose-dependent manner, by 8-51%. However, only 4-AP reduced proliferation of the MAT-LyLu cell line. Tetrodotoxin (6 microM) blocked completely the voltage-gated Na(+) channel expressed selectively in the MAT-LyLu cell line, but had no effect on the proliferation of either cell line. On the other hand, the presumed Na(+) channel "opener" veratridine (10-50 microM) reduced significantly, in a dose-dependent manner, the proliferation of both cell lines by up to approximately 30%.


CONCLUSIONS
We conclude that the mechanism(s) controlling the proliferation of the weakly metastatic AT-2 cells involves voltage-gated K(+) channels. In contrast, the proliferation of strongly metastatic MAT-LyLu cells is much less dependent upon voltage-gated K(+) channel activity.
Fraser
S P
SP
Neurobiology Group, Department of Biology, Imperial College of Science, Technology and Medicine, London, UK. s.p.fraser@ic.ac.uk
Grimes
J A
JA
Djamgoz
M B
MB
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D018999:Charybdotoxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005562:Formazans / Q000737:chemistry; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000473:pathology*; D051381:Rats; D012604:Scorpion Venoms; D015222:Sodium Channels / Q000187:drug effects*; D013778:Tetrazolium Salts / Q000737:chemistry; D013779:Tetrodotoxin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D005562:Formazans; D009498:Neurotoxins; D015221:Potassium Channels; D012604:Scorpion Venoms; D015222:Sodium Channels; D013778:Tetrazolium Salts; D018999:Charybdotoxin; C079782:MTT formazan; D013779:Tetrodotoxin; C077910:margatoxin; D014701:Veratridine; D015761:4-Aminopyridine; D014700:Verapamil