Leukemia, 2007-03, Vol.21 (3), p.535-540
2007
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- Autor(en) / Beteiligte
- Titel
- Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of β-catenin/TCF pathway
- Ist Teil von
- Leukemia, 2007-03, Vol.21 (3), p.535-540
- Ort / Verlag
- London: Nature Publishing
- Erscheinungsjahr
- 2007
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0887-6924eISSN: 1476-5551DOI: 10.1038/sj.leu.2404561Titel-ID: cdi_proquest_miscellaneous_69032491
- Format
- –
- Schlagworte
- Adenosine diphosphate, Antineoplastic Agents - pharmacology, Apoptosis, Apoptosis - drug effects, beta Catenin - antagonists & inhibitors, Biological and medical sciences, Bone marrow, Bortezomib, Caspase-8, Cell Line, Tumor - drug effects, Chronic lymphocytic leukemia, Clinical trials, Control, Cysteine Proteinase Inhibitors - pharmacology, Cytotoxicity, Dexamethasone, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Enantiomers, Etodolac - pharmacology, Gene Expression Regulation, Neoplastic - drug effects, Genetic aspects, Growth factors, Health aspects, Hematologic and hematopoietic diseases, Heterocyclic Compounds, 3-Ring - pharmacology, Humans, Immunodeficiencies. Immunoglobulinopathies, Immunoglobulinopathies, Immunopathology, Insulin, Insulin-like growth factor I, Insulin-Like Growth Factor I - antagonists & inhibitors, Insulin-Like Growth Factor I - pharmacology, Interleukin 6, Interleukin-6 - antagonists & inhibitors, Interleukin-6 - pharmacology, Leukemia, Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis, Lymphatic leukemia, Lymphocytes T, Medical sciences, Melphalan, Multiple myeloma, Multiple Myeloma - pathology, Myc protein, Neoplasm Proteins - antagonists & inhibitors, Nuclear transport, Poly(ADP-ribose) Polymerases - metabolism, Ribose, Risk factors, Signal Transduction - drug effects, Stromal cells, Survivin, TCF Transcription Factors - antagonists & inhibitors, Toxicity, Transcription factors, Translocation, Tumor cells, β-Catenin