Cancer-Selective Targeting of the NF-κB Survival Pathway with GADD45β/MKK7 Inhibitors
| Autor: | Laura Tornatore, Annamaria Sandomenico, Domenico Raimondo, Caroline Low, Alberto Rocci, Cathy Tralau-Stewart, Daria Capece, Daniel D’Andrea, Marco Bua, Eileen Boyle, Mark van Duin, Pietro Zoppoli, Albert Jaxa-Chamiec, Anil K. Thotakura, Julian Dyson, Brian A. Walker, Antonio Leonardi, Angela Chambery, Christoph Driessen, Pieter Sonneveld, Gareth Morgan, Antonio Palumbo, Anna Tramontano, Amin Rahemtulla, Menotti Ruvo, Guido Franzoso |
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| Přispěvatelé: | Tornatore, L, Sandomenico, A, Raimondo, D, Low, C, Rocci, A, Tralau Stewart, C, Capece, D, D'Andrea, D, Bua, M, Boyle, E, van Duin, M, Zoppoli, P, Jaxa Chamiec, A, Thotakura, Ak, Dyson, J, Walker, Ba, Leonardi, Antonio, Chambery, A, Driessen, C, Sonneveld, P, Morgan, G, Palumbo, A, Tramontano, A, Rahemtulla, A, Ruvo, M, Franzoso, G. |
| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Cancer Cell |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccell.2014.11.021 |
| Popis: | Summary Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β 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 GADD45β/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 myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit. Highlights • GADD45β is a critical mediator of the NF-κB antiapoptotic function in MM • GADD45β binds to MKK7 and promotes MM cell survival by blocking MKK7/JNK signaling • GADD45β/MKK7 inhibitors display potent activity against MM, in vitro and in vivo • GADD45β/MKK7 inhibitors are far more cancer selective than IKK/NF-κB inhibitors NF-κB is implicated in MM and other malignancies, but it is challenging to block NF-κB only in diseased cells. Tornatore et al. identify an interaction between MKK7 and NF-κB-regulated GADD45β as a therapeutic target and develop a peptide that disrupts the complex and selectively kills MM cells. |
| Databáze: | OpenAIRE |
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