title: In vivo and in vitro cytotoxicity of R-etodolac with dexamethasone in glucocorticoid-resistant multiple myeloma cells.
abstract: Glucocorticoids have been widely used in the treatment of multiple myeloma (MM) both as single agents and in combination with other drugs. However, primary or acquired glucocorticoid resistance occurs in most cases. It was recently reported that R-etodolac induced in vitro cytotoxicity in MM cell lines and in primary MM cells, as well as synergistically enhanced dexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells. This study examined the in vitro and in vivo effects of combination treatment with R-etodolac and Dex on Dex-resistant OPM1 cells. Treatment with R-etodolac and Dex was found to enhance cytotoxicity, inhibit nuclear factor kappaB activity via upregulation of IkappaBalpha, as well as enhance Dex-induced caspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells. R-etodolac also enhanced Dex cytotoxicity in patient MM cells that were resistant to glucocorticoids. The in vivo anti-tumour effect of this combination on MM cells was evaluated by using severe combined immunodeficient mice engrafted with OPM1. Treatment with R-etodolac or Dex alone did not induce a significant reduction of tumour volume; in contrast, combination treatment with R-etodolac and Dex induced significant synergistic inhibition of tumour growth. These data indicate that R-etodolac overcomes resistance to Dex in glucocorticoid-resistant MM cells, providing the framework for clinical trials of R-etodolac combined with Dex, to improve patient outcome in MM.
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Neri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Laurence P
authors.initials: LP
authors.lastname: Catley
authors.forename: Catley P
authors.initials: CP
authors.lastname: Laurence
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Simona
authors.initials: S
authors.lastname: Blotta
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Sarath
authors.initials: S
authors.lastname: Kanekal
authors.forename: Gary T
authors.initials: GT
authors.lastname: Elliott
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D024202:Electrophoretic Mobility Shift Assay; D017308:Etodolac / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D017308:Etodolac; D003907:Dexamethasone; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases