Exploring Inhibitory Mechanisms of Green Tea Catechins as Inhibitors of a Cancer Therapeutic Target, Nuclear Factor-κB (NF-κB)

Introduction

Cancer is one of the major chronic diseases worldwide, and every year 12.7 million new incidences are recorded. This number is expected to reach 26 million by 2030¹. The emerging targeted therapies provide a lot of hope, whereby a single target protein or enzyme is blocked using an inhibitor. The accumulating evidence established nuclear factor kappa B (NF-κB) as an excellent cancer therapeutic target^{2, 3}. The NF-κB, which acts as a transcription factor, exists in the form of homo or heterodimeric complex. These complexes are made up of Rel-like domain including proteins RelA (p65), RelB, p105 (NFκB1), (p50) NFκB1, Rel and p52 (NFκB2), and the complex from two different subunits p65 and p50 seems to be the major one. NF-κB’s linkage with cancer is shown through the constitutive activation of NF-κB in several types of cancer like breast, lung, liver, pancreatic, prostate and various kinds of lymphoma^4-9. The most important role of NF-κB is its ability to promote cell survival through the transcription of target pro-survival genes, resulting in protein expression that inhibits the programmed cell death (PCD) mechanism in both types of malignant and normal cells^{10, 11}. Due to the broad significance of NF-κB, it has been challenging to target NF-κB in cancer cells¹². Last few years’ studies have unveiled that NF-κB is activated by carcinogens, chemotherapeutic agents, tumour promoters, and by inflammatory cytokines¹³. Studies on preclinical models have shown that several chemotherapy drugs like taxanes, anthracyclines and platinum-based agents induce the activation of NF-κB pathway¹⁴, while there are a majority of drugs identified to be the inhibitor of NF-κB signaling, with potencies as low as 20nM. Some of these drugs like narasin, sunitinib malate, lestaurtinib, tribromsalan, bithionol, fluorosalan and emetine inhibit NF-κB signaling via inhibition of IkBa phosphorylation.¹⁵

The natural compounds have increasingly been exploited by the scientific community for anticancer potential.^16,19 In this view, green tea catechins were extensively studied for anticancer mechanisms controlling cell proliferation, cell death in tumour cells and vascular angiogenesis in solid tumours.^20,21 Recent studies have suggested that natural compounds catechins found in green tea have inhibitory activity against the NF-κB²². There are four major components in green...