Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer

NF-κB comprises a family of inducible transcription factors that serve as important regulators of the host immune and inflammatory response. In addition, NF-κB is also involved in protecting cells from undergoing apoptosis in response to DNA damage or cytokine treatment. Stimulation of the NF-κB pathway is mediated by diverse signal transduction cascades. These signals activate the IκB kinases, IKKα and IKKβ, which phosphorylate inhibitory proteins known as IκB to result in their ubiquitination and degradation by the proteasome. The degradation of IκB results in the translocation of NF-κB from the cytoplasm to the nucleus where it activates the expression of specific cellular genes. As we better understand the regulation of the NF-κB pathway, the potential for inhibiting this pathway has received attention. Agents that inhibit this pathway, such as glucocorticoids and aspirin, can reduce the inflammatory response, while other agents such as dominant negative IκB proteins potentiate the effects of chemotherapy and radiation therapy in the treatment of cancer. Here, we discuss cellular genes and disease states associated with activation of the NF-κB pathway and consider therapeutic strategies to prevent the prolonged activation of the NF-κB pathway.