Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of beta-catenin/TCF pathway.
We have reported previously that R-enantiomer of etodolac (R-etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of etodolac, has more potent cytotoxicity than R-etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits beta-catenin/T-cell factor pathway by inhibiting nuclear translocation of beta-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel etodolac analog SDX-308 can target MM cells in the BM milieu.
Yasui
H
H
Jerome Lipper Multiple-Myeloma Center, Department of Medical-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Hideshima
T
T
Ikeda
H
H
Ocio
E M
EM
Kiziltepe
T
T
Vallet
S
S
Okawa
Y
Y
Neri
P
P
Sukhdeo
K
K
Podar
K
K
Chauhan
D
D
Richardson
P G
PG
Raje
N
N
Carrasco
D R
DR
Anderson
K C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D017308:Etodolac / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D017308:Etodolac; D006575:Heterocyclic Compounds, 3-Ring; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D009363:Neoplasm Proteins; D011065:Poly(ADP-ribose) Polymerases; D051820:TCF Transcription Factors; D051176:beta Catenin; D000093242:Interleukin-6 Inhibitors; C495270:CTNNB1 protein, human; C518129:SDX 308