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Synthesis and antitumor properties of selenocoxib-1 against rat prostate adenocarcinoma cells.

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 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.
AuthorsDhimant Desai, Indu Sinha, Kevin Null, William Wolter, Mark A Suckow, Tonya King, Shantu Amin, Raghu Sinha
JournalInternational journal of cancer (Int J Cancer) Vol. 127 Issue 1 Pg. 230-8 (Jul 01 2010) ISSN: 1097-0215 [Electronic] United States
PMID19918950 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Organoselenium Compounds
  • Sulfonamides
  • selenocoxib-1
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Selenium
Topics
  • Adenocarcinoma (pathology)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Cyclooxygenase 1 (metabolism)
  • Cyclooxygenase 2 (metabolism)
  • Magnetic Resonance Spectroscopy
  • Male
  • Organoselenium Compounds (pharmacology)
  • Prostatic Neoplasms (pathology)
  • Rats
  • Rats, Wistar
  • Selenium (blood)
  • Sulfonamides (pharmacology)

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