NEOPLASIA SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma

In this study we report that R-etodolac (SDX-101), at clinically relevant concentra-tions, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)–, doxorubicin (Dox40/RPMI8226)–, and bort-ezomib (DHL4)–resistant cell lines. Immu-noblot analysis demonstrates that R-etodolac induces apoptosis characterized by caspase-8,-9, and-3 and PARP (poly-ADP [adenosine diphosphate]–ribose polymerase) cleavage and down-regula-tion of cyclin D1 expression. Subcyto-toxic doses of R-etodolac up-regulate my-eloid cell leukemia-1 proapoptotic variant (Mcl-1S), while enhancing dexametha-sone (Dex)–induced caspase activation and apoptosis. The combination of R-etodolac with Dex results in a highly synergistic cytotoxic effect. R-etodolac also induces apoptosis against primary cells isolated from patients with MM re-fractory to chemotherapy. Although inter-leukin 6 (IL-6) and insulin-like growth factor-1 (IGF-1) abrogate Dex-induced MM cell cytotoxicity, neither IL-6 nor IGF-1 protects against R-etodolac–induced cy-totoxicity in MM cells. R-etodolac also inhibits viability of MM cells adherent to bone marrow stromal cells (BMSCs), thereby overcoming a mechanism of drug resistance commonly observed with other conventional chemotherapeutic agents. Our data, therefore, indicate that R-etodolac circumvents drug resistance in MM cells at clinically relevant concen-trations, targets Mcl-1, and can be syner-gistically combined with Dex. (Blood