|
|
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.
 Previous Article | Next Article 
Submitted March 1, 2005
Accepted March 29, 2005
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*
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Salmedix, Inc., San Diego, CA, USA
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
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/-3 and PARP (poly-ADP-ribose polymerase) cleavage and down-regulation of cyclin D1 expression. Sub-cytotoxic doses of R-etodolac up-regulate 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 MM patients refractory to chemotherapy. Although IL-6 and IGF-1 abrogate Dex-induced MM cell cytotoxicity, neither protects against R-etodolac induced cytotoxicity in MM cells. R-etodolac also inhibits viability of MM cells adherent to bone marrow stromal cells (BMSC) 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
New aspects of myeloma management
- Angelo Vacca
Blood 2005 106: 395.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
B. Barlogie, G. Tricot, J. Haessler, F. van Rhee, M. Cottler-Fox, E. Anaissie, J. Waldron, M. Pineda-Roman, R. Thertulien, M. Zangari, et al.
Cytogenetically defined myelodysplasia after melphalan-based autotransplantation for multiple myeloma linked to poor hematopoietic stem-cell mobilization: the Arkansas experience in more than 3000 patients treated since 1989
Blood,
January 1, 2008;
111(1):
94 - 100.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Feng, G. Anderson, G. Xiao, G. Elliott, L. Leoni, M. Y. Mapara, G. D. Roodman, and S. Lentzsch
SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-{kappa}B activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth
Blood,
March 1, 2007;
109(5):
2130 - 2138.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
