Anticancer activity of a cyclooxygenase inhibitor, CX9051, in human prostate cancer cells: the roles of NF-κB and crosstalk between the extrinsic and intrinsic apoptotic pathways

Abstract

Comprehensive studies support the notion that selective inhibitors of cyclooxygenase-2 (COX-2) display anticancer activities in numerous types of cancer cells, including prostate cancers. Our previous study showed that the benzodithiazolium-based compound CX9051 selectively inhibited COX-2 activity. We now show that CX9051 inhibits cell proliferation and induces apoptosis in numerous human cancer cell types. Biochemical analyses, including flow cytometry, showed that CX9051 induced apoptosis in the absence of cell cycle checkpoint arrest and down-regulated the expression of Bcl-2, Bcl-x(L), and Mcl-1, but up-regulated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression, leading to proteolytic activation of caspase-8, -9, -7, and -3. These data suggest that CX9051 functions in both mitochondria-mediated intrinsic and death receptor-induced extrinsic apoptosis pathways. Moreover, confocal microscopy demonstrated that CX9051 induced nuclear translocation of nuclear factor-kappa B (NF-kappaB) at initial stage and then caused a marked decrease of total cellular NF-kappaB at later stage in both PC-3 and DU145 cells. Taken together, our data suggest that CX9051 induces TRAIL up-regulation and activation of extrinsic apoptotic signaling, which in turn activates mitochondria-mediated intrinsic apoptotic signaling, leading to cancer cell apoptosis.