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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. [ABSTRACT FROM AUTHOR]

Nuclear factor kappa B (NF-κB) transcription factors are evolutionarily conserved, coordinating regulators of immune and inflammatory responses. They also play a pivotal role in oncogenesis and metabolic disorders. Several studies during the past two decades have highlighted the key role of the IKK/NF-κB pathway in the induction and maintenance of the state of inflammation that underlies metabolic diseases such as obesity and type 2 diabetes. Recent reports, however, reveal an even more intimate connection between NF-κB and metabolism. These studies demonstrate that NF-κB regulates energy homeostasis via direct engagement of the cellular networks governing glycolysis and respiration, with profound implications beyond metabolic diseases, including cancer, ageing and anticancer therapy. In this review, we discuss these emerging bioenergetic functions of NF-κB and their significance to oncogenesis. [ABSTRACT FROM AUTHOR]

Abstract: NF-κB transcription factors are evolutionarily conserved, central coordinators of immune and inflammatory responses. They also play a pivotal role in oncogenesis. NF-κB exerts these functions by regulating the transcription of genes encoding many immunoregulators, inflammatory mediators and inhibitors of apoptosis. Several studies during the past few years have also underscored the key role of the IKK/NF-κB pathway in the induction and maintenance of the state of inflammation that underlies metabolic pathologies such as obesity, insulin resistance and type-2 diabetes, reflecting the co-evolution and integration of nutrient- and pathogen-sensing systems. Recent reports, however, are revealing an even more intimate, direct connection between NF-κB and metabolism. These studies demonstrate that NF-κB regulates energy homeostasis via direct engagement of the cellular networks governing glycolysis and respiration, with profound implications that extend beyond metabolic pathologies, to cellular physiology, cancer, and anti-cancer therapy. In this review article, we discuss these emerging metabolic functions of NF-κB and their significance to oncogenesis and cancer treatment. [Copyright &y& Elsevier]

Constitutive NF-κB signalling has been implicated in the pathogenesis of most human malignancies and virtually all non-malignant pathologies. Accordingly, the NF-κB pathway has been aggressively pursued as an attractive therapeutic target for drug discovery. However, the severe on-target toxicities associated with systemic NF-κB inhibition have thus far precluded the development of a clinically useful, NF-κB-targeting medicine as a way to treat patients with either oncological or non-oncological diseases. This minireview discusses some of the more promising approaches currently being developed to circumvent the preclusive safety liabilities of global NF-κB blockade by selectively targeting pathogenic NF-κB signalling in cancer, while preserving the multiple physiological functions of NF-κB in host defence responses and tissue homeostasis. [ABSTRACT FROM AUTHOR]