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Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products.
Blood. 2007 Oct 01; 110(7):2286-95.Blood

Abstract

Salinosporamide A (also called NPI-0052), 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 poorly understood mechanism. Here we demonstrate that salinosporamide A potentiated the apoptosis induced by tumor necrosis factor alpha (TNF), bortezomib, and thalidomide, and this correlated with down-regulation of gene products that mediate cell proliferation (cyclin D1, cyclooxygenase-2 [COX-2], and c-Myc), cell survival (Bcl-2, Bcl-xL, cFLIP, TRAF1, IAP1, IAP2, and survivin), invasion (matrix metallopro-teinase-9 [MMP-9] and ICAM-1), and angiogenesis (vascular endothelial growth factor [VEGF]). Salinosporamide A also suppressed TNF-induced tumor cell invasion and receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis. We also found that it suppressed both constitutive and inducible NF-kappaB activation. Compared with bortezomib, MG-132, N-acetyl-leucyl-leucyl-norleucinal (ALLN), and lactacystin, salinosporamide A was found to be the most potent suppressor of NF-kappaB activation. Further studies showed that salinosporamide A inhibited TNF-induced inhibitory subunit of NF-kappaB alpha (IkappaBalpha) degradation, nuclear translocation of p65, and NF-kappaB-dependent reporter gene expression but had no effect on IkappaBalpha kinase activation, IkappaBalpha phosphorylation, or IkappaBalpha ubiquitination. Thus, overall, our results indicate that salinosporamide A enhances apoptosis, suppresses osteoclastogenesis, and inhibits invasion through suppression of the NF-kappaB pathway.

Authors+Show Affiliations

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17609425

Citation

Ahn, Kwang Seok, et al. "Salinosporamide a (NPI-0052) Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion Through Down-modulation of NF-kappaB Regulated Gene Products." Blood, vol. 110, no. 7, 2007, pp. 2286-95.
Ahn KS, Sethi G, Chao TH, et al. Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products. Blood. 2007;110(7):2286-95.
Ahn, K. S., Sethi, G., Chao, T. H., Neuteboom, S. T., Chaturvedi, M. M., Palladino, M. A., Younes, A., & Aggarwal, B. B. (2007). Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products. Blood, 110(7), 2286-95.
Ahn KS, et al. Salinosporamide a (NPI-0052) Potentiates Apoptosis, Suppresses Osteoclastogenesis, and Inhibits Invasion Through Down-modulation of NF-kappaB Regulated Gene Products. Blood. 2007 Oct 1;110(7):2286-95. PubMed PMID: 17609425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products. AU - Ahn,Kwang Seok, AU - Sethi,Gautam, AU - Chao,Ta-Hsiang, AU - Neuteboom,Saskia T C, AU - Chaturvedi,Madan M, AU - Palladino,Michael A, AU - Younes,Anas, AU - Aggarwal,Bharat B, Y1 - 2007/07/03/ PY - 2007/7/5/pubmed PY - 2007/11/7/medline PY - 2007/7/5/entrez SP - 2286 EP - 95 JF - Blood JO - Blood VL - 110 IS - 7 N2 - Salinosporamide A (also called NPI-0052), 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 poorly understood mechanism. Here we demonstrate that salinosporamide A potentiated the apoptosis induced by tumor necrosis factor alpha (TNF), bortezomib, and thalidomide, and this correlated with down-regulation of gene products that mediate cell proliferation (cyclin D1, cyclooxygenase-2 [COX-2], and c-Myc), cell survival (Bcl-2, Bcl-xL, cFLIP, TRAF1, IAP1, IAP2, and survivin), invasion (matrix metallopro-teinase-9 [MMP-9] and ICAM-1), and angiogenesis (vascular endothelial growth factor [VEGF]). Salinosporamide A also suppressed TNF-induced tumor cell invasion and receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis. We also found that it suppressed both constitutive and inducible NF-kappaB activation. Compared with bortezomib, MG-132, N-acetyl-leucyl-leucyl-norleucinal (ALLN), and lactacystin, salinosporamide A was found to be the most potent suppressor of NF-kappaB activation. Further studies showed that salinosporamide A inhibited TNF-induced inhibitory subunit of NF-kappaB alpha (IkappaBalpha) degradation, nuclear translocation of p65, and NF-kappaB-dependent reporter gene expression but had no effect on IkappaBalpha kinase activation, IkappaBalpha phosphorylation, or IkappaBalpha ubiquitination. Thus, overall, our results indicate that salinosporamide A enhances apoptosis, suppresses osteoclastogenesis, and inhibits invasion through suppression of the NF-kappaB pathway. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/17609425/Salinosporamide_A__NPI_0052__potentiates_apoptosis_suppresses_osteoclastogenesis_and_inhibits_invasion_through_down_modulation_of_NF_kappaB_regulated_gene_products_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)60475-X DB - PRIME DP - Unbound Medicine ER -