Therapeutic approaches targeting prostate cancer progression using novel voltage-gated ion channel blockers.
The early detection and treatment of prostate cancer have increased survival and improved clinical outcomes. The nature of the disease and pathologic understaging result in a high proportion of patients developing locally recurrent disease or distant metastases. The development of prostate cancer the time from tumor initiation and progression to invasive carcinoma often begins in men in the fourth or fifth decades of life and extends across decades. This prolonged window highlights the tremendous clinical impact that early intervention with therapeutic agents that selectively target the invasive and metastatic potential of the prostate cancer cell could have on patient survival and quality of life. Our research is currently focused on the development and testing of novel voltage-gated ion channel blockers. The expression of voltage-gated sodium channels (VGSCs) was recently associated with the metastatic behavior of prostate cancer cells. In these studies, VGSC blockers altered prostate cancer cell morphology and arrested prostate cancer cell migration. Clinically, one of the most widely used sodium channel blockers is phenytoin. We have used rational drug design based on the phenytoin binding site in a VGSC to make novel sodium channel blockers with enhanced activity and minimal acute toxicity. Our initial studies in vitro demonstrate enhanced binding of the compounds to the sodium channel and increased inhibition of prostate cancer cell growth in culture and in soft agarose compared with phenytoin. These derivatives are currently being tested for their antitumor activity in human prostate cancer xenografts.
Sikes
Robert A
RA
Laboratory for Cancer Ontogeny and Therapeutics, Department of Biological Sciences, 330 Wolf Hall, University of Delaware, Newark, DE 19716, USA. rasikes@udel.edu
Walls
Alison M
AM
Brennen
W Nathaniel
WN
Anderson
James D
JD
Choudhury-Mukherjee
Indrani
I
Schenck
Hilary A
HA
Brown
Milton L
ML
D000230:Adenocarcinoma / Q000503:physiopathology / Q000628:therapy*; D015195:Drug Design; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D011471:Prostatic Neoplasms / Q000503:physiopathology / Q000628:therapy*; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000502:physiology
D026941:Sodium Channel Blockers; D015222:Sodium Channels