Son of Celebrex

A relative of the anti-inflammatory drug Celebrex appears uniquely adept at impairing or halting tumor growth.

By Lori Oliwenstein

A close structural relative of the celebrated COX-2 inhibitor celecoxib (brand name Celebrex) is a potent tumor-fighter, able to wipe out tumor cells that are resistant to conventional chemotherapies, according to an interdisciplinary team of researchers.

Led by Axel H. Schönthal, Ph.D., associate professor of molecular microbiology and immunology at the Keck School of Medicine of USC, the researchers have been studying the effects of an analog of celecoxib. The analog does not have its cousin’s celebrated ability to block the activity of cyclooxygenase-2 (COX-2), an enzyme integral to the inflammatory process. Nonetheless, the scientists showed that the analog manages to halt tumor growth even in drug-resistant lines of multiple myeloma cells.

The work was published in the Dec. 15 issue of the journal Blood.

Most of the recent attention garnered by celecoxib has come as a result of its anti-inflammatory effects and the withdrawal of the two other COX-2 inhibitors on the market—Vioxx and Bextra—after data linked them to an increased risk of stroke in some patients. Only Celebrex remains on the market.

But celecoxib is more than just an anti-inflammatory agent. Researchers have begun to recognize that COX-2 can sometimes play a role in cancer; for instance, they have shown that the enzyme is overexpressed by multiple myeloma cells, and this is a predictor of a poor outcome for the patient. Researchers reasoned that a COX-2 inhibitor might be able to turn things around.

It did. In laboratory studies, the COX-2 inhibitor celecoxib showed an ability to target several of the growth pathways. Further studies, including some by Schönthal and his colleagues, showed that celecoxib’s anticancer activity appeared to be independent from its COX-2 inhibition. Schönthal’s team went on to show that the analog in question—2,5-dimethyl-celecoxib, or DMC—retains the ability to stop cancer growth despite the fact that it does not inhibit the activity of COX-2.

The researchers noted in the Blood paper that “growth-inhibitory effects take place even in cells that otherwise are highly resistant to the inhibitory effects of various anti-cancer drugs.”

The fact that DMC is as potent—or possibly more potent, even at lower doses—than celecoxib despite having no ability to inhibit COX-2, is important, especially in light of the side effects of COX-2 inhibitory drugs. “Bearing in mind that substantially increased daily dosages of these drugs are considered for cancer prevention or cancer therapy, the increased risk of cardiovascular failure is of considerable concern,” the researchers wrote in the Blood paper. But because the unwanted cardiovascular side effects of celecoxib are connected to its ability to inhibit COX-2, Schönthal speculates that DMC, which lacks that ability, might not cause similar problems.

Schönthal notes that his research points to celecoxib as being unique in its ability to slow or stop tumor growth. All the COX-2 inhibitors are able to block the activity of cyclooxygenase-2, he says, but only celecoxib and its analogs seem able to arrest growth and induce cellular suicide (apoptosis), even in cells that do not produce COX-2.

It will be important to extend these current results, Schönthal says. “Proof of principle has been established with this work, so our next goal will be to evaluate DMC in myeloma patients, perhaps in combination with other drugs.”

 

This work was funded by grants from the James H. Zumberge Faculty Research and Innovation Fund and from the Margaret E. Early Medical Research Trust