Digoxin Inhibits Blood Vessel Density and HIF‐1a Expression in Castration‐Resistant C4‐2 Xenograft Prostate Tumors

PURPOSE: Recent studies suggest a potential application for digoxin in the prevention and/or treatment of prostate cancer. However, the effect of digoxin on androgen receptor (AR)-positive prostate tumor in vivo is not clear. This study is designed to determine if digoxin can inhibit AR-positive xenograft prostate tumors. MATERIALS AND METHODS: Athymic male nude mice were utilized to establish subcutaneous C4-2 castration-resistant prostate tumors. The animals were castrated and then treated with daily intraperitoneal (i.p.) injection of digoxin at 2 mg/kg along with vehicle controls for 7 consecutive days. Tumor growth was determined by measuring tumor volume changes, blood vessel density by immunostaining of CD31, and cell proliferation by BrdU labeling. The expression of HIF-1α in C4-2 tumors was measured by Western blot and real-time RT-PCR. RESULTS: Digoxin inhibited blood vessel density about fourfold and down-regulated HIF-1α expression at both mRNA and protein levels. However, digoxin did not inhibit C4-2 tumor growth. CONCLUSIONS: Digoxin is a potent inhibitor of HIF-1α signaling pathway and blood vessel formation in C4-2 castration-resistant prostate tumors.