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3-Phosphoinositide-Dependent Protein Kinase-1/Akt Signaling Represents a Major Cyclooxygenase-2-Independent Target for Celecoxib in Prostate Cancer Cells

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio

Regarding the involvement of cyclooxygenase-2 (COX-2)-independent pathways in celecoxib-mediated antineoplastic effects, the following two issues remain outstanding: identity of the non-COX-2 targets and relative contributions of COX-2-dependent versus -independent mechanisms. We use a close celecoxib analog deficient in COX-2-inhibitory activity, DMC {4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide}, to examine the premise that Akt signaling represents a major non-COX-2 target. Celecoxib and DMC block Akt activation in PC-3 cells through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1) with IC₅₀ of 48 and 38 µM, respectively. The consequent effect on Akt activation is more pronounced (IC₅₀ values of 28 and 20 µM, respectively), which might be attributed to the concomitant dephosphorylation by protein phosphatase 2A. In serum-supplemented medium, celecoxib and DMC cause G₁ arrest, and at higher concentrations, they induce apoptosis with relative potency comparable with that in blocking Akt activation. Moreover, the effect of daily oral celecoxib and DMC at 100 and 200 mg/kg on established PC-3 xenograft tumors is assessed. Celecoxib at both doses and DMC at 100 mg/kg had marginal impacts. However, a correlation exists between the in vitro potency of DMC and its ability at 200 mg/kg to inhibit xenograft tumor growth through the inhibition of Akt activation. Analysis of the tumor samples indicates that a differential reduction in the phospho-Akt/Akt ratio was noted in celecoxib- and DMC-treated groups vis-à-vis the control group. Together, these data underscore the role of 3-phosphoinositide-dependent protein kinase-1/Akt signaling in celecoxib-mediated in vitro antiproliferative effects in prostate cancer cells.

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