SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-κB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth

Rentian Feng, Gülsüm Anderson, Guozhi Xiao, Gary Elliott, Lorenzo Leoni, Markus Y. Mapara, G. David Roodman, Suzanne Lentzsch

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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-κB activation and osteoclast formation in an osteoclast cellular model, RAW264.7. SDX-308 effectively suppressed TNF-α-induced IKK-α and IκB-α phosphorylation and degradation and subsequent NF-κB 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-κB 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.

Original languageEnglish (US)
Pages (from-to)2130-2138
Number of pages9
JournalBlood
Volume109
Issue number5
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

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Cell growth
Non-Steroidal Anti-Inflammatory Agents
Osteoclasts
Multiple Myeloma
Growth
Bone
Etodolac
Chemical activation
Cell proliferation
Bone Resorption
Cell Proliferation
Bone and Bones
Phosphorylation
B-Cell Chronic Lymphocytic Leukemia
Dentin
SDX 308
Osteogenesis
Pharmaceutical Preparations
Assays
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Hematology

Cite this

SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-κB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth. / Feng, Rentian; Anderson, Gülsüm; Xiao, Guozhi; Elliott, Gary; Leoni, Lorenzo; Mapara, Markus Y.; Roodman, G. David; Lentzsch, Suzanne.

In: Blood, Vol. 109, No. 5, 01.03.2007, p. 2130-2138.

Research output: Contribution to journalArticle

Feng, Rentian ; Anderson, Gülsüm ; Xiao, Guozhi ; Elliott, Gary ; Leoni, Lorenzo ; Mapara, Markus Y. ; Roodman, G. David ; Lentzsch, Suzanne. / SDX-308, a nonsteroidal anti-inflammatory agent, inhibits NF-κB activity, resulting in strong inhibition of osteoclast formation/activity and multiple myeloma cell growth. In: Blood. 2007 ; Vol. 109, No. 5. pp. 2130-2138.
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abstract = "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-κB activation and osteoclast formation in an osteoclast cellular model, RAW264.7. SDX-308 effectively suppressed TNF-α-induced IKK-α and IκB-α phosphorylation and degradation and subsequent NF-κB 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-κB 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.",
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