title: Overexpression of cyclooxygenase-2 in malignant peripheral nerve sheath tumor and selective cyclooxygenase-2 inhibitor-induced apoptosis by activating caspases in human malignant peripheral nerve sheath tumor cells.
abstract: BACKGROUND
  Cyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST.
  
  
  METHODS
  We evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1.
  
  
  RESULTS
  Overexpression of COX-2 (≥50% positive cells) was observed in 29 cases (65.9%), was significantly associated with a poor overall survival (P = 0.0495), and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis.
  
  
  CONCLUSIONS
  Selective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses.
authors: Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan ; Department of Pathology and Diagnostic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Michiyuki
authors: M
authors: Hakozaki
authors: Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Takahiro
authors: T
authors: Tajino
authors: Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Shinichi
authors: S
authors: Konno
authors: Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors: Shinichi
authors: S
authors: Kikuchi
authors: Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Hitoshi
authors: H
authors: Yamada
authors: Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Aomori, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Michiro
authors: M
authors: Yanagisawa
authors: Department of Orthopaedic Surgery, School of Medicine, Iwate Medical University, Iwate, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Jun
authors: J
authors: Nishida
authors: Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Hiroyuki
authors: H
authors: Nagasawa
authors: Department of Orthopaedic Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Takashi
authors: T
authors: Tsuchiya
authors: Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan ; Tohoku Musculoskeletal Tumor Society, Yamagata, Japan.
authors: Akira
authors: A
authors: Ogose
authors: Department of Pathology and Diagnostic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors: Masafumi
authors: M
authors: Abe
authors: Department of Pathology and Diagnostic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors: Hiroshi
authors: H
authors: Hojo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017308:Etodolac / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018317:Nerve Sheath Neoplasms / Q000201:enzymology* / Q000473:pathology*; D055815:Young Adult
chemical_list: D061945:Caspase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D017308:Etodolac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020169:Caspases