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

Blood. 2005 Jul 15;106(2):706-12. doi: 10.1182/blood-2005-02-0838. Epub 2005 Mar 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / pathology
  • Caspases / metabolism
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cyclin D1 / metabolism
  • Dexamethasone / administration & dosage*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Etodolac / administration & dosage
  • Etodolac / chemistry
  • Etodolac / pharmacology*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Interleukin-6 / pharmacology
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Stereoisomerism


  • Antineoplastic Agents
  • Interleukin-6
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Cyclin D1
  • Etodolac
  • Insulin-Like Growth Factor I
  • Dexamethasone
  • Poly(ADP-ribose) Polymerases
  • Caspases