1. ¹Jerome Lipper Multiple–Myeloma Center, Department of Medical–Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
2. ²First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
3. ³Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
4. ⁴Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA

Correspondence: Professor KC Anderson, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Mayer 557, Boston, MA 02115, USA. E-mail: kenneth_anderson@dfci.harvard.edu

Received 11 September 2006; Revised 29 November 2006; Accepted 30 November 2006; Published online 1 February 2007.

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 -catenin/T-cell factor pathway by inhibiting nuclear translocation of -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.