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Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of beta-catenin/TCF pathway.

Abstract
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.
AuthorsH Yasui, T Hideshima, H Ikeda, E M Ocio, T Kiziltepe, S Vallet, Y Okawa, P Neri, K Sukhdeo, K Podar, D Chauhan, P G Richardson, N Raje, D R Carrasco, K C Anderson
JournalLeukemia (Leukemia) Vol. 21 Issue 3 Pg. 535-40 (Mar 2007) ISSN: 0887-6924 [Print] England
PMID17268521 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • CTNNB1 protein, human
  • Cysteine Proteinase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Interleukin-6
  • Neoplasm Proteins
  • SDX 308
  • TCF Transcription Factors
  • beta Catenin
  • Etodolac
  • Insulin-Like Growth Factor I
  • Poly(ADP-ribose) Polymerases
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Cell Line, Tumor (drug effects)
  • Cysteine Proteinase Inhibitors (pharmacology)
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Etodolac (pharmacology)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Heterocyclic Compounds, 3-Ring (pharmacology)
  • Humans
  • Insulin-Like Growth Factor I (antagonists & inhibitors, pharmacology)
  • Interleukin-6 (antagonists & inhibitors, pharmacology)
  • Multiple Myeloma (pathology)
  • Neoplasm Proteins (antagonists & inhibitors)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Signal Transduction (drug effects)
  • TCF Transcription Factors (antagonists & inhibitors)
  • beta Catenin (antagonists & inhibitors)

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