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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2286-2295.
Prepublished online as a Blood First Edition Paper on August 1, 2007July 3, 2007; DOI 10.1182/blood-2007-04-084996.
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Submitted April 11, 2007
Accepted June 28, 2007
Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through downmodulation of NF- B-regulated gene products
Kwang Seok Ahn, Gautam Sethi, Madan M. Chaturvedi, Michael A. Palladino, Anas Younes, and Bharat B. Aggarwal*
Cytokine Research Lab, Dept of Experimental Therapeutis, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Nereus Pharmaceuticals, San Diego, CA, United States
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: aggarwal{at}mdanderson.org.
Salinosporamide A (also called NPI-0052), a lactone recently identified from the marine bacterium Salinispora tropica, is a potent inhibitor of 20S proteasome and exhibits therapeutic potential against a wide variety of tumors through a mechanism that is not fully understood. In the present study, we demonstrate that salinosporamide A potentiated the apoptosis induced by TNF, Velcade and thalidomide, and this correlated with downregulation of various gene products that mediate cell proliferation (cyclin D1, COX-2, and c-Myc), cell survival (Bcl-2, Bcl-xL, cFLIP, TRAF1, IAP1, IAP2, and survivin), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). Salinosporamide A also suppressed TNF-induced tumor cell invasion and RANKL-induced osteoclastogenesis. Since most of these cellular responses require NF- B activation, we found that the lactone suppressed both constitutive and inducible NF-B activation. When compared with other proteasome inhibitors such as Velcade, MG-132, ALLN, and lactacystin, salinosporamide A was found to be the most potent suppressor of NF-B activation. Further studies showed that salinosporamide A inhibited TNF-induced IB degradation, nuclear translocation of p65, and NF-B-dependent reporter gene expression but had no effect on IB kinase activation, IB phosphorylation or on IB ubiquitination. Thus, overall, our results indicate that salinosporamide A enhances apoptosis, suppresses osteoclastogenesis, and inhibits invasion through suppression of NF-B pathway.
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