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Cancer-selective targeting of the NF-?B survival pathway with GADD45?/MKK7 inhibitors.

ABSTRACT: Constitutive NF-?B signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-?B-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-?B-regulated antiapoptotic factor GADD45? 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?/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-?B pathway is possible and, at least for myeloma patients, promises a profound benefit.

SUBMITTER: Tornatore L 

PROVIDER: S-EPMC4197335 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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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. DT  ...[more]

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