Voltage-gated sodium channel blockers as cytostatic inhibitors of the androgen-independent prostate cancer cell line PC-3.
The recent discovery of sodium (Na(+)) channel expression in human prostate cancer (PCa) cells led us to investigate the potential use of neuronal Na(+) channel blockers as inhibitors of PCa cells. Our initial studies discovered two classes of Na(+) channel blockers that were effective inhibitors of PCa cell proliferation. Both hydroxyamides (compounds 1 and 4) and a hydantoin (compound 5) were shown to inhibit the androgen-independent PCa cell line PC-3 in vitro. Electrophysiology showed that all compounds functionally block brain type II voltage-gated Na(+) channels (Nav1.2) expressed in Xenopus laevis oocytes. Long-term growth assays in androgen-independent PC-3 cells showed remarkable inhibition of cell growth, with cells growing to a maximum of 30% of controls with analogue 1. Further, our analogues demonstrated only marginal impact on cell viability over the same treatment interval.
Anderson
James D
JD
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Hansen
Todd P
TP
Lenkowski
Paul W
PW
Walls
Alison M
AM
Choudhury
Indrani M
IM
Schenck
Hilary A
HA
Friehling
Mati
M
Höll
Genevieve M
GM
Patel
Manoj K
MK
Sikes
Robert A
RA
Brown
Milton L
ML
D000728:Androgens / Q000502:physiology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004594:Electrophysiology; D006801:Humans; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010672:Phenytoin / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D014981:Xenopus
D000728:Androgens; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010672:Phenytoin