Inflammation and Cancer: When NF-κB Amalgamates the Perilous Partnership

Marina   A.   Dobrovolskaia; Serguei   V.   Kozlov

Abstract

Chronic inflammation has long been suggested to constitute a risk factor for a variety of epithelial cancers such as malignancies of prostate, cervix, esophagus, stomach, liver, colon, pancreas, and bladder. An inflammatory response is typically accompanied by generation of free radicals, stimulation of cytokines, chemokines, growth and angiogenic factors. Free radicals, capable of both directly damaging DNA and affecting the DNA repair machinery, enhance genetic instability of affected cells, thus contributing to the first stage of neoplastic transformation also known as "initiation". Cytokines and growth factors can further promote tumor growth by stimulating cell proliferation, adhesion, vascularization, and metastatic potential of later stage tumors. Nuclear factor kappa B (NF-κB) is a family of ubiquitously expressed transcription factors that are widely believed to trigger both the onset and the resolution of inflammation. NF-κB also governs the expression of genes encoding proteins essential in control of stress response, maintenance of intercellular communications, and regulation of cellular proliferation and apoptosis. Recent data have expanded the concept of inflammation as a critical component in carcinogenesis suggesting new anti-inflammatory therapies for a complementary approach in treating a variety of tumor types. These observations highlighted the NF-κB pathway as an attractive avenue for drug discovery and development. The present review will outline recent advances in our understanding of NF-κB function in the inflammatory processes and its input in tumor initiation/promotion, as well as summarize the development of animal and cell culture models for validating drug candidates with NF- κB-modulating activities, and applications of the latter in cancer therapy.

Keywords: inflammation, cancer, drug discovery, drug development, cell-based assays

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