Anticancer drug reveals alternate means of inducing cell suicide

Derivatives of the COX-2 inhibitor celecoxib can trigger cancer cell suicide, or apoptosis, but not necessarily through the recognized means of blocking COX-2 enzyme activity, a new study concludes. By separating COX-2 activity from apoptosis, researchers have a starting point for designing new classes of anticancer drugs, write Xueqin Song, Ching-Shih Chen, Ph.D., Ohio State University, and their coworkers in the April 17 issue of the Journal of the National Cancer Institute.

Celecoxib, an anti-inflammation pill for arthritis, is being studied for its potential in preventing and treating certain cancers. In a large percentage of tumors, the COX-2 enzyme is elevated, say Ernest T. Hawk, M.D., M.P.H., of the National Cancer Institute, and his coworkers in an accompanying editorial. They point out that past studies have shown that decreasing levels of COX-2 can suppress the growth of tumors. However, it has been unclear whether celecoxib’s anticancer effects depend on COX-2 inhibition alone.

To find out, Chen and his coworkers created prostate cancer cells lacking the COX-2 enzyme. In contrast to the effects of COX-2 inhibitors such as celecoxib, which induce cell death, cells that lacked COX-2 remained alive. Exposure of these cells lacking COX-2 to various COX-2 inhibitors did lead to cell death. What’s more, derivatives of celecoxib that did not block COX-2 activity also caused cell death.

The authors note that these events were associated not with levels of COX-2 but with decreased phosphorylation of Akt and ERK2 proteins. This mode of action differs from that of conventional anticancer drugs, they point out.

In the accompanying editorial, Hawk and his colleagues note that celecoxib is being tested for the treatment and prevention of colon cancer and that newer generations of COX-2 inhibitors could prove to be safer and more effective.

However, they point out that the current findings are based on concentrations of celecoxib that are higher than clinically achievable. For these findings to translate into new mechanisms of cell death, the study should be repeated at clinically achievable doses of celecoxib, the editorialists note. They add that the drugs also must target cancer cells, not normal cells.

Contact: Michelle Gailiun, Ohio State University Medical Center, (614) 293-6054; fax: (614) 293-3730, gailiun.1@osu.edu

Editorial: NCI Office of Communications, (301) 496-6641; Fax: (301) 496-0846, ncipressofficers@mail.nih.gov

Song X, Lin H, Johnson AJ, Tseng P, Yang Y, Kulp SK, Chen C. Cyclooxygenase-2, Player or Spectator in Cyclooxygenase-2 Inhibitor-Induced Apoptosis in Prostate Cacner Cells. J Natl Cancer Inst 2002;94:585–91.

Editorial: Hawk ET, Viner JL, Dannenberg A, DuBois RN. Cox-2 in cancer—A player that’s defining the rules. J Natl Cancer Inst 2002;94:545–6.

Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

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