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.
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Authors | H 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 |
Journal | Leukemia
(Leukemia)
Vol. 21
Issue 3
Pg. 535-40
(Mar 2007)
ISSN: 0887-6924 [Print] England |
PMID | 17268521
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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