TY - JOUR
T1 - Targeting IκappaB kinases for cancer therapy
AU - Awasthee, Nikee
AU - Rai, Vipin
AU - Chava, Srinivas
AU - Nallasamy, Palanisamy
AU - Kunnumakkara, Ajaikumar B.
AU - Bishayee, Anupam
AU - Chauhan, Subhash C.
AU - Challagundla, Kishore B.
AU - Gupta, Subash C.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2019/6
Y1 - 2019/6
N2 - The inhibitory kappa B kinases (IKKs)and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed.
AB - The inhibitory kappa B kinases (IKKs)and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed.
KW - Cancer therapy
KW - IKK inhibitor
KW - IKK related kinase
KW - Inhibitory kappa B kinase
KW - Nuclear factor kappa B
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U2 - 10.1016/j.semcancer.2018.02.007
DO - 10.1016/j.semcancer.2018.02.007
M3 - Review article
C2 - 29486318
AN - SCOPUS:85042865881
SN - 1044-579X
VL - 56
SP - 12
EP - 24
JO - Seminars in Cancer Biology
JF - Seminars in Cancer Biology
ER -