Extensive research during last two decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, cardiovascular, neurological and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.

Activation of nuclear factor (NF)-κB, one of the most investigated transcription factors, has been found to control multiple cellular processes in cancer including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance and radioresistance. NF-κB is constitutively active in most tumor cells, and its suppression inhibits the growth of tumor cells, leading to the concept of ‘NF-κB addiction’ in cancer cells. Why NF-κB is constitutively and persistently active in cancer cells is not fully understood, but multiple mechanisms have been delineated including agents that activate NF-κB (such as viruses, viral proteins, bacteria and cytokines), signaling intermediates (such as mutant receptors, overexpression of kinases, mutant oncoproteins, degradation of IκBα, histone deacetylase, overexpression of transglutaminase and iNOS) and cross talk between NF-κB and other transcription factors (such as STAT3, HIF-1α, AP1, SP, p53, PPARγ, β-catenin, AR, GR and ER). As NF-κB is ‘preactive’ in cancer cells through unrelated mechanisms, classic inhibitors of NF-κB (for example, bortezomib) are unlikely to mediate their anticancer effects through suppression of NF-κB. This review discusses multiple mechanisms of NF-κB activation and their regulation by multitargeted agents in contrast to monotargeted agents, thus ‘one size does not fit all’ cancers.

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IntroductionAlthough plant-derived products have served humankind as treatments of various ailments for centuries, neither their active components nor their molecular targets are fully understood. Identifying the active chemical entities and their molecular targets can lead to discovering new clinical uses of such products, as in the cases of vincristine, vinblastine, paclitaxel, camptothecin, roscovitin, and homoharringtonine. 1 Between 1980 and 2000, as many as 70% of all drugs approved by the US Food and Drug Administration to treat cancer were based on natural sources. 1,2 Gambogic acid (GA) is a naturally occurring brownish-toorange resin called gamboge, which is derived from Garcinia hanburyi. It has a long history of medicinal use in Southeast Asia, and it is used as a folk medicine and coloring agent in China. Recent studies showed that GA can inhibit the growth of a wide variety of tumor cells, including cells of human hepatoma, 3 breast cancer, 4 gastric carcinoma, 5-8 and lung carcinoma. 9 Using cell-and caspase-based high-throughput screening assays, Zhang et al identified GA as a potent inducer of apoptosis. 4 Studies have also indicated that GA suppresses the growth of human tumors (eg, lung carcinoma, 9 and hepatoma). 3 How GA mediates these effects is not fully understood, but it has been shown to inhibit telomerase and telomerase reverse transcriptase mRNA expression, 3,8,9 inhibit human telomerase reverse transcriptase (hTERT) promoter, 8 suppress cyclin-dependent kinase 7 (CDK7)-mediated phosphorylation of CDC2/34, 7 down-regulate Bcl-2, 5 and interact with c-Myc. 3 A recent report suggests that GA mediates its apoptotic effects through its interaction with the transferrin receptor (TfR1). 10 Because hTERT, c-Myc, and Bcl-2 gene expression modulated by GA is regulated by NF-B activation, it is possible that GA mediates its effects by modulating the NF-B pathway.NF-B is a transcription factor that consists of 5 proteins: c-Rel, RelA (p65), RelB, NF-B1 (p50 and p105), and NF-B2 (p52). 11 They are regulated by inhibitors of the inhibitory subunit of NF-B (IB) family of anchorin domain-containing proteins, which includes IB␣, IB␤, IB␥, IB⑀, Bcl-3, p105, and p100. 11 When inactive, NF-B is sequestered in the cytoplasm as a heterotrimer consisting of p50, p65, and IB subunits. Most carcinogens, inflammatory agents, and tumor promoters, including cigarette smoke, phorbol ester, okadaic acid, H 2 O 2 , and tumor necrosis factor (TNF), have been shown to activate NF-B. In response to an activation signal, the IB␣ subunit is phosphorylated at serine residues 32 and 36, ubiquitinated at lysine residues 21 and 22, and degraded through the proteasomal pathway, thus exposing the nuclear localization signals on the p50-p65 heterodimer. The p65 is then phosphorylated, leading to nuclear translocation and binding to a specific sequence in DNA, which in turn results in gene transcription. The phosphorylation of IB␣ is catalyzed by IB␣ kinase (IKK), which is essential for NF-B activation. IKK consists of 3 subun...