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Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.

  • Tornatore L Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
  • Sandomenico A Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy.
  • Raimondo D Department of Physics, "Sapienza" University, 00185 Rome, Italy.
  • Low C Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
  • Rocci A Division of Hematology, University of Torino, AOU San Giovanni Battista, 10126 Turin, Italy.
  • Tralau-Stewart C Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
  • Capece D Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
  • D'Andrea D Department of Physics, "Sapienza" University, 00185 Rome, Italy.
  • Bua M Department of Medicine, Centre for Haematology, Imperial College London, London W12 0NN, UK.
  • Boyle E Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
  • van Duin M Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
  • Zoppoli P Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
  • Jaxa-Chamiec A Drug Discovery Centre, Imperial College London, London W6 8RP, UK.
  • Thotakura AK Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.
  • Dyson J Department of Medicine, Section of Molecular Immunology, Imperial College London, London W12 0NN, UK.
  • Walker BA Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
  • Leonardi A Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II," 80131 Naples, Italy.
  • Chambery A Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, Second University of Naples, 81100 Caserta, Italy; IRCCS Multimedica, 20138 Milan, Italy.
  • Driessen C Department of Oncology/Hematology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
  • Sonneveld P Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
  • Morgan G Section of Haemato-Oncology, The Institute of Cancer Research, London SM2 5NG, UK.
  • Palumbo A Division of Hematology, University of Torino, AOU San Giovanni Battista, 10126 Turin, Italy.
  • Tramontano A Department of Physics, "Sapienza" University, 00185 Rome, Italy; Istituto Pasteur Fondazione Cenci Bolognetti, "Sapienza" University, 00185 Rome, Italy.
  • Rahemtulla A Department of Medicine, Centre for Haematology, Imperial College London, London W12 0NN, UK.
  • Ruvo M Institute of Biostructures and Bioimages, National Research Council and CIRPeB, 80134 Naples, Italy. Electronic address: menotti.ruvo@unina.it.
  • Franzoso G Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK. Electronic address: g.franzoso@imperial.ac.uk.
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  • 2014-10-15
Published in:
  • Cancer cell. - 2014
Antineoplastic Agents
Biological Availability
Cell Cycle Proteins
Humans
MAP Kinase Kinase 7
Multiple Myeloma
NF-kappa B
Nuclear Proteins
English 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.
Language
  • English
Open access status
hybrid
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Persistent URL
https://sonar.ch/global/documents/278239
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