Abstract
Hormone refractory prostate cancer poses a huge problem and standard of care chemotherapy has not been very successful. We used a novel strategy to combine properties of 2 well‐studied class of compounds (selenium and COX‐2 inhibitor) and examined the resulting effectiveness against prostate cancer. Bearing in mind that sulfonamide moiety and pyrazole ring is important for the proapoptotic activity of Celecoxib, we synthesized a selenium derivative, Selenocoxib‐1, by modifying Celecoxib at position 3 of the pyrazole ring. The PAIII cells derived from a metastatic prostate tumor that arose spontaneously in a Lobund‐Wistar (LW) rat were used to examine the efficacy of Selenocoxib‐1 in vitro. In addition, human metastatic prostate cancer cells, PC‐3M, were tested for antitumor effect of Selenocoxib‐1 in vitro. The IC~50~ in PAIII and PC‐3M cells for Selenocoxib‐1 was about 5 μM, while for Celecoxib it was more than 20 μM. Selenocoxib‐1 induced apoptosis in a dose‐dependent manner in the PAIII cells. COX‐2 expression in PAIII cells was downregulated by Celecoxib and Selenocoxib‐1 at 20 and 5 μM, respectively; the COX‐2 activity was, however, not affected by Selenocoxib‐1. Following treatment with Selenocoxib‐1, PAIII cells resulted in dose‐dependent decrease in HIF‐1α, p‐AKT and Bcl‐2 levels. A reduction in weights was observed in subcutaneous tumors produced by PAIII cells pretreated with Selenocoxib‐1 as compared to Celecoxib in LW rats. Further, following 1 week Selenocoxib‐1 treatment of PAIII tumors resulted in significant reduction of tumor weights. This study demonstrates that Selenocoxib‐1 is more effective against prostate cancer than Celecoxib.