title: Etodolac induces apoptosis and inhibits cell adhesion to bone marrow stromal cells in human myeloma cells.
abstract: OBJECTIVE
  Cyclooxygenase-2 (COX-2) is reported to regulate apoptosis and to be an important cellular target for therapy.
  
  
  METHODS
  We examined whether etodolac, meloxicam, and thalidomide inhibited proliferation and induced apoptosis in myeloma cell lines (RPMI 8226 and MC/CAR cells).
  
  
  RESULTS
  Etodolac induced apoptosis more strongly compared with thalidomide or meloxicam. Etodolac induced down-regulation of Bcl-2 protein and mRNA, activation of Caspase-9, -7 and -3, cIAP-1 and Survivin, and loss of mitochondrial membrane potential in a dose-dependent manner. In addition, when myeloma cells were coincubated with 50 microM etodolac on bone marrow stromal cells (BMSCs), myeloma cell adhesion to BMSCs was significantly inhibited compared with thalidomide or meloxicam coincubation, and the adhesion molecules VLA-4, LFA-1 (CD11a), CXCX4, and CD44 were suppressed on myeloma cells treated with etodolac. Moreover, 50-100 microM racemate of etodolac significantly inhibited the proliferation of myeloma cells compared to 100 microM R-etodolac or S-etodolac.
  
  
  CONCLUSIONS
  Etodolac induced loss of mitochondrial membrane potential and apoptosis via a COX-2-independent pathway, suppressed the expression of adhesion molecules, and inhibited myeloma cell adhesion to BMSCs compared with thalidomide or meloxicam. The activities of etodolac potentially extend to the treatment of patients with myeloma resistant to standard chemotherapy, including thalidomide.
authors.affiliation: Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan. satonaka@hama-med.ac.jp
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Miki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Shibata
authors.forename: Naohi
authors.initials: N
authors.lastname: Sahara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shigeno
authors.forename: Kaori
authors.initials: K
authors.lastname: Shinjo
authors.forename: Kensuke
authors.initials: K
authors.lastname: Naito
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D017308:Etodolac / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism; D017154:Stromal Cells / Q000187:drug effects; D013792:Thalidomide / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017308:Etodolac; D013792:Thalidomide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone