Multiple myeloma is characterized by increased osteoclast activity that results in bone destruction and lytic lesions. With the prolonged overall patient 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 nonsteroidal 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 that is already used in clinical trials for the treatment of
B-cell chronic lymphocytic leukemia (B-CLL). Compared with SDX-101, a 10-fold lower concentration of
SDX-308 induced potent (60%-80%) inhibition 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-kappaB activation and osteoclast formation in an osteoclast cellular model, RAW 264.7.
SDX-308 effectively suppressed
TNF-alpha-induced
IKK-gamma and
IkappaB-alpha phosphorylation and degradation and subsequent
NF-kappaB 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-kappaB activation signaling. We propose that
SDX-308 is a promising therapeutic candidate to inhibit
multiple myeloma growth and osteoclast activity and that it should receive attention for further study.