Synthesis and antitumor properties of selenocoxib-1 against rat prostate adenocarcinoma cells.
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.
Desai
Dhimant
D
Penn State College of Medicine, Penn State Hershey Cancer Institute, Hershey, PA 17033, USA.
Sinha
Indu
I
Null
Kevin
K
Wolter
William
W
Suckow
Mark A
MA
King
Tonya
T
Amin
Shantu
S
Sinha
Raghu
R
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D012643:Selenium / Q000097:blood; D013449:Sulfonamides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D013449:Sulfonamides; C549961:selenocoxib-1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D012643:Selenium