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 microM, while for
Celecoxib it was more than 20 microM.
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 microM, 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-1alpha, 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.