title: Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.
authors: College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea.
authors: Jong Kyu
authors: JK
authors: Woo
authors: Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors: Ju-Hee
authors: JH
authors: Kang
authors: College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea.
authors: Yeong-Su
authors: YS
authors: Jang
authors: Crystal Genomics, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors: Seonggu
authors: S
authors: Ro
authors: Crystal Genomics, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors: Joong Myung
authors: JM
authors: Cho
authors: College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea.
authors: Hwan-Mook
authors: HM
authors: Kim
authors: Crystal Genomics, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors: Sang-Jin
authors: SJ
authors: Lee
authors: College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea.
authors: Seung Hyun
authors: SH
authors: Oh
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007417:Intestinal Polyps / Q000517:prevention & control; D007421:Intestine, Small / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D053320:Receptors, Tumor Necrosis Factor, Member 10c / Q000096:biosynthesis / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000096:biosynthesis / Q000235:genetics; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; C000599293:CG100649; D005663:Furans; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors