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Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-κB pathways

Key Points

  • p53 is the most extensively studied tumor suppressor deregulated in most human cancers.

  • It is stimulated by various activating stimuli such as DNA damage, oncogene activation, stress and hypoxia.

  • Much effort has focused on studying activation of p53 for cancer therapy and various small-molecule activators have been identified so far. Some approaches for p53 activation for therapy include MDM2 inhibition and CDK inhibition.

  • Hyperactivation of the NF-κB pathway is seen in many cancers and inflammatory disorders.

  • The NF-κB pathway is activated by more 200 stimuli including viruses, cytokines, stress, bacterial or fungal products.

  • Efforts have focused on identifying inhibitors of the NF-κB pathway with over 785 inhibitors identified so far and counting.

  • There is a lot of interest in understanding the crosstalk between these two critical signalling pathways, which have been implicated in various human ailments.

  • With combination therapy emerging as the way forward in cancer therapy, small molecules that simultaneously target both these pathways by activating p53 and inhibiting NF-κB hold great promise for cancer therapy.

  • This Review focuses on candidate small molecules that have these dual desirable properties and suggests mechanism of action and prospects for future development.

Abstract

The p53 and nuclear factor-κB (NF-κB) pathways play crucial roles in human cancer, in which inactivation of p53 and hyperactivation of NF-κB is a common occurrence. Activation of p53 and inhibition of NF-κB promotes apoptosis. Although drugs are being designed to selectively activate p53 or inhibit NF-κB, there is no concerted effort yet to deliberately make drugs that can simultaneously do both. Recent results suggest that a surprising selection of small molecules have this desirable dual activity. In this Review we describe the principles behind such dual activities, describe the current candidate molecules and suggest mechanisms and approaches to their further development.

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Figure 1: The p53 pathway.
Figure 2: The NF-κB pathway.
Figure 3: Proposed models for bifunctional activity of small molecules.
Figure 4: Classes of compounds that simultaneously activate p53 and inhibit NF-κB.

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Acknowledgements

The authors apologize to all those whose primary work could not be cited owing to space limitations. This work is supported by the Agency for Science, Technology and Research (A*STAR), Singapore. D.P.L. is a Gibb Fellow of Cancer Research UK.

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Dey, A., Tergaonkar, V. & Lane, D. Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-κB pathways. Nat Rev Drug Discov 7, 1031–1040 (2008). https://doi.org/10.1038/nrd2759

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