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The Aryl Propionic Acid R-Flurbiprofen Selectively Induces p75^NTR-Dependent Decreased Survival of Prostate Tumor Cells

¹ Department of Biochemistry and Molecular & Cellular Biology and the ² Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, and ³ Myriad Pharmaceuticals Inc., Salt Lake City, Utah

Requests for reprints: Daniel Djakiew, Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road, N.W., Washington, DC 20057-1436. Phone: 202-687-1203; Fax: 202-687-1823; E-mail: djakiewd{at}georgetown.edu.

Epidemiologic studies show that patients chronically consuming nonsteroidal anti-inflammatory drugs (NSAID) for arthritis exhibit a reduced incidence of prostate cancer. In addition, some NSAIDs show anticancer activity in vitro. NSAIDs exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX) activity; however, evidence suggests that COX-independent mechanisms mediate decreased prostate cancer cell survival. Hence, we examined the effect of selected aryl propionic acid NSAIDs and structurally related compounds on the decreased survival of prostate cancer cell lines PC-3, DU-145, and LNCaP by induction of the p75^NTR protein. p75^NTR has been shown to function as a tumor suppressor in the prostate by virtue of its intracellular death domain that can initiate apoptosis and inhibit growth. The most efficacious compounds for induction of p75^NTR and decreased survival, in rank-order, were R-flurbiprofen, ibuprofen, oxaprozin, fenoprofen, naproxen, and ketoprofen. Because R-flurbiprofen and ibuprofen exhibited the greatest efficacy, we examined their dose-dependent specificity of induction for p75^NTR relative to other members of the death receptor family. Whereas treatment with R-flurbiprofen or ibuprofen resulted in a massive induction of p75^NTR protein levels, the expression of Fas, p55^TNFR, DR3, DR4, DR5, and DR6 remained largely unchanged. Moreover, transfection of either cell line before R-flurbiprofen or ibuprofen treatment with a dominant negative form of p75^NTR to antagonize p75^NTR activity or p75^NTR small interfering RNA to prevent p75^NTR protein expression rescued both cell lines from decreased survival. Hence, R-flurbiprofen and ibuprofen selectively induce p75^NTR-dependent decreased survival of prostate cancer cells independently of COX inhibition. [Cancer Res 2007;67(7):3254–62]

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