Submitted July 5, 2006
Accepted October 10, 2006
SDX-308, a non-steroidal anti-inflammatory agent, inhibits NF-
B activity resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth
Rentian Feng, Gulsum Anderson, Guozhi Xiao, Gary Elliott, Lorenzo Leoni, Markus Y Mapara, G. David Roodman, and Suzanne Lentzsch*
Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA
Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA
Galenic Strategies Consulting Services, San Diego, CA
Mondobiotech, Gentilino, Switzerland
* Corresponding author; email: lentzschs{at}upmc.edu.
Multiple myeloma is characterized by increased osteoclast activity resulting in bone destruction and lytic lesions. With prolonged overall survival achieved by new treatment modalities, additional drugs are required to inhibit bone destruction. We focused on a novel and more potent structural analog of the non-steroidal anti-inflammatory drug etodolac known as SDX-308, and its effects on osteoclastogenesis and multiple myeloma cells. SDX-101 is another structural analog of etodolac already used in clinical trials for the treatment of B-CLL. Compared to SDX-101, a 10-fold lower concentration of SDX-308 induced a potent inhibition (60-80%) of osteoclast formation, and a 10- to 100-fold lower concentration inhibited multiple myeloma cell proliferation. Bone resorption was completely inhibited by SDX-308 as determined in dentin-based bone resorption assays. SDX-308 decreased constitutive and RANKL-stimulated NF-
B activation and osteoclast formation by an osteoclast cellular model, RAW 264.7. It effectively suppressed TNF-
-induced IKK-
and IkB- phosphorylation and degradation and subsequent NF-B activation in human multiple myeloma cells. These results indicate that SDX-308 effectively inhibits multiple myeloma cell proliferation and osteoclast activity, potentially by controlling NF-B activation signaling. We propose that SDX-308 is a promising therapeutic candidate to inhibit multiple myeloma growth and osteoclast activity, and should receive attention for further study.
