USC researchers find drug is tough tumor fighter

August 29, 2005

Los Angeles, Aug. 29, 2005 - 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 from the University of Southern California.

Led by Axel H. Schšnthal, 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 that 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. (Multiple myeloma is an incurable cancer of the plasma cell; plasma cells are components of the blood, and play a key role in the body's immune response.)

The work was published in the most recent online edition of the journal Blood, and will be appearing in an upcoming print edition of the journal.

Most of the attention celecoxib has received in recent years has been as a result of its anti-inflammatory effects and, most recently, the withdrawal of the two other main COX-2 inhibitors on the market-Vioxx and Bextra-after data unearthed linking them to an increased risk of stroke in some patients. (Celebrex remains on the market, but now carries a "black box" warning about the potential for cardiovascular side effects.)

But the truth is, celecoxib is more than just an anti-inflammatory agent. Over the past couple of years, researchers have begun to recognize that cyclooxygenase-2 can sometimes play a role in cancer; for instance, they've shown that the enzyme is overexpressed by multiple myeloma cells, and that this is a predictor of a poor outcome for the patient. Thus, it seemed clear that a cylooxygenase inhibitor might be able to turn things around.

It did. In several laboratory studies, the COX-2 inhibitor celecoxib showed an ability to target several of the growth pathways; further studies, including some performed by Schšnthal and colleagues, showed that celecoxib's anticancer activity appeared to be independent from its COX-2 inhibition. Schšnthal's team then 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 doesn't inhibit the activity of COX-2.

"Amazingly," the researchers noted in the Blood paper, "these growth-inhibitory effects take place even in cells that otherwise are highly resistant to the inhibitory effects of various anti-cancer drugs that are commonly used in the clinic for the treatment of cancer patients."

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

Schšnthal notes that his research points to celecoxib in particular 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 don't produce COX-2.

What does all this mean for the treatment of multiple myeloma? It will be important to extend these current results and determine whether these drugs achieve similar anti-tumor effects in myeloma patients, Schšnthal says. "Curing laboratory mice of multiple myeloma isn't good enough," he adds. "But 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.

Adel Kardosh, Nathalie Soriano, Yen-Ting Liu, Jasim Uddin, Nicos A. Petasis, Florence M. Hofman, Thomas C. Chen, Axel H. Schšnthal, "Multi-target inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2-inhibitory analog of celecoxib." Blood.

University of Southern California

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