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.

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance

“…This proinflammatory transcription factor plays an important role in the development and progression of cancer and its aberrant activation has been proposed as the major cause of chemoresistance through the activation of a multitude of mediators, including antiapoptotic genes (99). It has been shown that the sensitivity of colorectal cancer cells to oxaliplatin-induced death is adversely affected by elevated NF-kB activity (100) and that cell lines with acquired resistance to oxaliplatin showed increased activation of NF-kB (p65 subunit) as compared with their matched sensitive parental cells, implicating NF-kB as a potential mediator of oxaliplatin resistance acquisition in colorectal cancer (101,102).…”

In�vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway

“…One study demonstrated that NF-κB was persistently highly expressed in cisplatin-resistant ovarian cancer cells, and that it served an important role in drug resistance of ovarian cancer cells (5). NF-κB exerts anti-apoptotic effects via regulating downstream target proteins B-cell lymphoma (Bcl)-xL, Bcl-2, Fas/FasL, X-linked inhibitor of apoptosis protein, survivin, cellular inhibitor of apoptosis protein 1/2, cyclin-dependent kinase2, vascular endothelial growth factor and cyclooxygenase-2, whereby the viability of tumor cells is increased, resulting in chemotherapy resistance (8).…”

“…A previous study by our group revealed that 20-40 µmol/l naringin was able to significantly inhibit the proliferation of ovarian cancer cells resistant to platinum-based agents in vitro (7); however, the underlying mechanisms by which naringin reverses this resistance remain unclear. A previous study indicated that the nuclear factor (NF)-κB signaling pathway serves a role in the In vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway development and progression of ovarian cancer (8). The aim of the present study is to investigate the mechanism of action by which naringin inhibits the expression of P-glycoprotein (P-gp) in a cisplatin-resistant human epithelial ovarian cancer cell line (SKOV3/CDDP) from the perspective of NF-κB signal transduction, thereby providing an experimental rationale for the development and application of naringin as a treatment for ovarian cancer.…”

Strategic targeting of the PI3K–NFκB axis in cisplatin-resistant NSCLC

“…This study was performed on the basis of previous published evidence supporting a role for the PI3K-NFκB axis in cisplatin resistance, 3,[9][10][11][12][13] with the aim of identifying strategic points within this pathway to target in order to overcome this resistance in NSCLC. With this promising data implying a major role for IκBα/NFκB interaction in NSCLC cisplatin resistance, inhibition of NFκB by DHMEQ or other targeted inhibitors could provide a beneficial treatment strategy for NSCLC patients who progress on cisplatin.…”

“…The major mechanisms of resistance are (1) increased influx/decreased influx of cisplatin, (2) elevated levels of glutathione, (3) increased DNA repair, and (4) activation of signal transduction pathways, e.g., MAPK, AKT, and NFκB. [3][4][5] Phosphatidylinositol 3-kinases (PI3Ks) were discovered by Lewis Cantley and colleagues, who first published on their association with the polyoma middle T protein in 1985. 6 The signals that PI3K family members help to potentiate induce the cell to grow, differentiate, proliferate, and help with survival, motility, and intracellular trafficking.…”