Targeting nuclear factor-kappa B to overcome resistance to chemotherapy

Abstract

Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-κB pathway. NF-κB is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anti-cancer target. Here, we describe the role of NF-κB in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signaling by pharmacological intervention will be addressed.

Keywords: NF-κB; apoptosis; cancer; chemotherapy; cisplatin; oncogene; resistance.

Figure 1

Activation of NF-κB can be described by distinct pathways, according to the mechanism of IκB degradation. Canonical signaling, initiated by toll-like-receptor (TLR) ligation, is dependent on the IKK complex containing NF-κB essential modulator (NEMO) and IKKα/IKKβ. Non-canonical signaling occurs in response to ligation of a subset of tumor-necrosis factor receptor (TNFs) members, is dependent on the NF-κB-inducing kinase (NIK), which activates proteolytic processing of p100 by IKKα. NF- κB activation can also occur through a IKK-independent mechanism, induced by DNA damage detection, involving the serine threonine kinase casein kinase 2 (CK2), which activates the IκB targeting cysteine protease calpain.