Celecoxib Slows Prostate Cancer

COX-1 is considered a constitutive enzyme, being found in most mammalian cells. COX-2, on the other hand, is undetectable in most normal tissues. It is an inducible enzyme, becoming abundant in activated macrophages and other cells at sites of inflammation.

In terms of their molecular biology, COX-1 and COX-2 are of similar molecular weight (67 and 72 kDa, respectively), having 65% amino acid sequence homology and near-identical catalytic sites. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2. The relatively smaller valine residue in COX-2 allows access to a hydrophobic side-pocket in the enzyme (which isoleucine sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2. The two main drugs of this type are celexocib (Celebrex) and rofecoxib (Vioxx).

In the current study, investigators at Cornell University (Ithaca, NY, USA) worked with PC3 and LNCaP human prostate cancer cell lines that produce COX-1 but not COX-2. They found that treating the cells with clinical levels of celexocib inhibited the growth of both cell lines, whereas rofecoxib had no effect over the same concentration range. The growth inhibition was shown to be due to a decrease in amounts of cyclin D1 induced by G1 cell cycle blockage and reduction of DNA synthesis.

Treatment of animals with grafted human prostate tumors gave similar results. Animals receiving celexocib experienced up to a 52% reduction in tumor volume and about 50% decrease in both cell proliferation and microvessel density. Rofecoxib had no effect on the transplanted tumors. These findings were published in the March 2005 issue of Clinical Cancer Research.

"It is well established that COX-2 is a significant and rational target for anti-cancer therapy,” said senior author Dr. Andrew Dannenberg, director of cancer prevention at the Weill Medical College of Cornell University. "These studies suggest that celecoxib exerts a second mode of action independent of its known anti-inflammatory mechanism that imposes further restrictions on the proliferation of prostate cancer cells. The results provide potentially important insights into our understanding of the overall anti-tumor activity of selective COX-2 inhibitors.”





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