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 Blood, 15 July 2005, Vol. 106, No. 2, pp. 706-712.
Prepublished online as a Blood First Edition Paper on March 31, 2005; DOI 10.1182/blood-2005-02-0838.

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NEOPLASIA

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

Hiroshi Yasui, Teru Hideshima, Makoto Hamasaki, Aldo M. Roccaro, Norihiko Shiraishi, Shaji Kumar, Pierfrancesco Tassone, Kenji Ishitsuka, Noopur Raje, Yu-Tzu Tai, Klaus Podar, Dharminder Chauhan, Lorenzo M. Leoni, Sarath Kanekal, Gary Elliott, Nikhil C. Munshi, and Kenneth C. Anderson

From the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Salmedix, Inc, San Diego, CA; and the First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.

In this study we report that R-etodolac (SDX-101), at clinically relevant concentrations, induces potent cytotoxicity in drug-sensitive multiple myeloma (MM) cell lines, as well as in dexamethasone (MM.1R)-, doxorubicin (Dox40/RPMI8226)-, and bortezomib (DHL4)-resistant cell lines. Immunoblot 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-regulation of cyclin D1 expression. Subcytotoxic doses of R-etodolac up-regulate myeloid cell leukemia-1 proapoptotic variant (Mcl-1S), while enhancing dexamethasone (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 refractory to chemotherapy. Although interleukin 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 cytotoxicity 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 concentrations, targets Mcl-1, and can be synergistically combined with Dex. (Blood. 2005;106:706-712)


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