Anticancer activity of a cyclooxygenase inhibitor, CX9051, in human prostate cancer cells: the roles of NF-kappaB and crosstalk between the extrinsic and intrinsic apoptotic pathways.
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.
School of Pharmacy, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei 100, Taiwan.
Chiung-Hua
CH
Huang
Jih-Hwa
JH
Guh
Grace Shiahuy
GS
Chen
Pin-Hsuan
PH
Lu
Ji-Wang
JW
Chern
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D053218:Receptors, Death Domain / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
C548616:3-(4-bromophenyl)-6-nitrobenzo(1.3.2)dithiazolium ylide 1,1-dioxide; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D003499:Cyclic S-Oxides; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051546:Cyclooxygenase 2; D020169:Caspases