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Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors
- Source :
- Cancer Cell, 26(4), 495-508. Cell Press, Cancer cell, 26 (2014): 495–508. doi:10.1016/j.ccr.2014.07.027, info:cnr-pdr/source/autori:Tornatore, Laura; Sandomenico, Annamaria; Raimondo, Domenico; Low, Caroline; Rocci, Alberto; Tralau-Stewart, Cathy; Capece, Daria; D'Andrea, Daniel; Bua, Marco; Boyle, Eileen; van Duin, Mark; Zoppoli, Pietro; Jaxa-Chamiec, Albert; Thotakura, Anil K.; Dyson, Julian; Walker, Brian A.; Leonardi, Antonio; Chambery, Angela; Driessen, Christoph; Sonneveld, Pieter; Morgan, Gareth; Palumbo, Antonio; Tramontano, Anna; Rahemtulla, Amin; Ruvo, Menotti; Franzoso, Guido/titolo:Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta%2FMKK7 Inhibitors/doi:10.1016%2Fj.ccr.2014.07.027/rivista:Cancer cell (Print)/anno:2014/pagina_da:495/pagina_a:508/intervallo_pagine:495–508/volume:26
- Publication Year :
- 2014
-
Abstract
- Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.
- Subjects :
- EXPRESSION
BORTEZOMIB
Biological Availability
Antineoplastic Agents
Cell Cycle Proteins
MAP Kinase Kinase 7
MKK7/JNKK2
ACTIVATION
PROTEASOME INHIBITOR
INFLAMMATION
SDG 3 - Good Health and Well-being
MULTIPLE-MYELOMA
KINASE
Humans
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
mieloma multiplo
Science & Technology
NF-kappa B
Nuclear Proteins
Cell Biology
Oncology
CELLS
SIGNALING PATHWAY
Multiple Myeloma
1109 Neurosciences
Life Sciences & Biomedicine
Subjects
Details
- Language :
- English
- ISSN :
- 15356108
- Database :
- OpenAIRE
- Journal :
- Cancer Cell, 26(4), 495-508. Cell Press, Cancer cell, 26 (2014): 495–508. doi:10.1016/j.ccr.2014.07.027, info:cnr-pdr/source/autori:Tornatore, Laura; Sandomenico, Annamaria; Raimondo, Domenico; Low, Caroline; Rocci, Alberto; Tralau-Stewart, Cathy; Capece, Daria; D'Andrea, Daniel; Bua, Marco; Boyle, Eileen; van Duin, Mark; Zoppoli, Pietro; Jaxa-Chamiec, Albert; Thotakura, Anil K.; Dyson, Julian; Walker, Brian A.; Leonardi, Antonio; Chambery, Angela; Driessen, Christoph; Sonneveld, Pieter; Morgan, Gareth; Palumbo, Antonio; Tramontano, Anna; Rahemtulla, Amin; Ruvo, Menotti; Franzoso, Guido/titolo:Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta%2FMKK7 Inhibitors/doi:10.1016%2Fj.ccr.2014.07.027/rivista:Cancer cell (Print)/anno:2014/pagina_da:495/pagina_a:508/intervallo_pagine:495–508/volume:26
- Accession number :
- edsair.dedup.wf.001..81eef247a238dfaffeb8415075fcddb4