In vivo and in vitro cytotoxicity of R-etodolac with dexamethasone in glucocorticoid-resistant multiple myeloma cells.
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.
Neri
Paola
P
Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Yasui
Hiroshi
H
Hideshima
Teru
T
Tassone
Pierfrancesco
P
Raje
Noopur
N
Catley
Laurence P
LP
Laurence
Catley P
CP
Ishitsuka
Kenji
K
Blotta
Simona
S
Kiziltepe
Tanyel
T
Ocio
Enrique M
EM
Fulciniti
Mariateresa
M
Kanekal
Sarath
S
Elliott
Gary T
GT
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D017308:Etodolac; D003907:Dexamethasone; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases