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 IC(50) of 48 and 38 micro M, respectively. The consequent effect on Akt activation is more pronounced (IC(50) values of 28 and 20 micro M, respectively), which might be attributed to the concomitant dephosphorylation by
protein phosphatase 2A. In serum-supplemented medium,
celecoxib and DMC cause G(1) 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.