Novel Etodolac Analog SDX-308 (CEP-18082) Induces Cytotoxicity in Multiple Myeloma Cells Associated with Inhibition of Wnt/β-Catenin Pathway.

In a previous study we reported that R-enantiomer of etodolac (R-etodolac) which is under investigation in Phase II clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in both drug-sensitive and drug-resistant multiple myeloma (MM) cell lines, as well as in patient MM tumor cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of etodolac, has more potent cytotoxicity than R-etodolac against MM cell lines and tumor cells from patients with refractory MM. It also induces cytotoxicity against bortezomib-resistant tumor cells. The molecular mechanisms whereby SDX-308 triggers MM cell cytotoxicity were next delineated. SDX-308 induces apoptosis via caspase-8/-9/-3 activation and poly(ADP-ribose) polymerase PARP cleavage. It strongly inhibits Wnt/β-catenin pathway by blockade of nuclear translocation of β-catenin, followed by significant inhibition of transcription and expression of target proteins. These target proteins include cell cycle regulatory c-myc molecules and anti-apoptotic survivin molecules. Neither interleukin-6 nor insulin-like growth factor-1, which induce MM cell growth and abrogate Dex-induced apoptosis, 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 has more potent cytotoxicity in MM cells than R-etodolac even in the context with BM microenvironment, providing the preclinical rationale to conduct clinical trials of this agent to improve patient outcome in MM.