1044 Reviews Targeting Inflammatory Pathways by Flavonoids for Prevention and Treatment of Cancer Authors Sahdeo Prasad, Kannokarn Phromnoi, Vivek R. Yadav, Madan M. Chaturvedi, Bharat B. Aggarwal Affiliation Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA Key words Abstract formation, tumor cell survival, proliferation, inva- l" cancer ! sion, angiogenesis, and metastasis. Whereas vari- l" inflammation Observational studies have suggested that life- ous lifestyle risk factors have been found to acti- l" flavonoids style risk factors such as tobacco, alcohol, high- vate NF-κB and NF-κB-regulated gene products, l" NF‑κB fat diet, radiation, and infections can cause cancer flavonoids derived from fruits and vegetables l" fruits l" vegetables and that a diet consisting of fruits and vegetables have been found to suppress this pathway. The can prevent cancer. Evidence from our laboratory present review describes various flavones, flava- and others suggests that agents either causing or nones, flavonols, isoflavones, anthocyanins, and preventing cancer are linked through the regula- chalcones derived from fruits, vegetables, le- tion of inflammatory pathways. Genes regulated gumes, spices, and nuts that can suppress the by the transcription factor NF-κB have been proinflammatory cell signaling pathways and shown to mediate inflammation, cellular trans- thus can prevent and even treat the cancer. Introduction cancers and the observed changes in the inci- ! dence of cancer in migrating populations. For ex- Despite spending billions of dollars in research, a ample, Ho [4] showed that although the Chinese great deal of understanding of the causes and cell in Shanghai will have a cancer incidence of 2 cases signaling pathways that lead to the disease, can- per 100 000 population, among those who mi- cer continues to be a major killer worldwide. Ac- grate to the United States, the incidence increases cording to a recent statistical analysis, a total of to 23 per 100000 within 5 years. In contrast, 1479350 new cancer cases and 562340 deaths among US-born persons of Chinese descent the from cancer occurred in the United States in cancer incidence is 37 cases per 100 000 popula- received February 23, 2010 2009 [1]. Unlike heart disease, death rates for can- tions, compared with 58 per 100000 among revised June 8, 2010 cer remained approximately the same in the whites. This indicates that lifestyle plays a major accepted June 10, 2010 United States from 1975 through 2002. Indeed, it role in the development of cancer. The important Bibliography is predicted that by 2020 approximately 15 mil- lifestyle factors that affect the incidence and mor- DOI http://dx.doi.org/ lion new cancer cases will be diagnosed world- tality of cancer include tobacco, alcohol, diet, obe- 10.1055/s-0030-1250111 wide and 12 million cancer patients will die [2]. sity, infectious agents, environmental pollutants, Published online July 15, 2010 One of the most important findings to have and radiation. All of these risk factors are linked Planta Med 2010; 76: emerged during the past three decades is that to each other through inflammation. 1044–1063 © Georg Thieme Verlag KG Stuttgart · New York · cancer is a preventable disease. Thus, people need Inflammation is a localized reaction of tissue to ISSN 0032‑0943 to be educated about the risk factors for cancer infection, irritation, or other injury. As defined by and those that prevent the disease. As many as Rudolf Virchow in 1863, the key features of in- Correspondence Bharat B. Aggarwal 90% of all cancers have been shown to be due to flammation are redness, warmth, swelling, pain, M.D. Anderson Cancer Center environmental/acquired factors such as tobacco, and sometimes loss of movement or function. In- The University of Texas diet, radiation, and infectious organisms, etc., flammation is a necessary response to clear viral 1515 Holcombe Blvd. – Box 143 and only the remaining 5 10% of cases are caused infections, repair tissue insults, and suppress tu- Houston, TX 77030 by internal factors such as inherited mutations, mor initiation/progression. However, when in- USA hormones, and immune conditions [3]. flammation persists or control mechanisms are Phone: + 17137941817 Fax: + 171 37456339 A strong link between diet and cancer is indicated dysregulated, disease may develop, including [email protected] by the large variation in incidence rates of specific cancer. Interestingly, inflammation functions at Prasad S et al. Targeting Inflammatory Pathways… Planta Med 2010; 76: 1044–1063 Reviews 1045 all three stages of tumor development: initiation, progression, survival, invasion, and angiogenesis. Those that can suppress car- and metastasis. During the initiation phase, inflammation indu- cinogenesis are discussed in detail below. ces the release of a variety of cytokines and chemokines that pro- mote the activation of inflammatory cells and associated factors. This causes further oxidative damage, DNA mutations, and other Association of Inflammation with Cancer changes in the tissue microenvironment, making it more condu- ! cive to cell transformation, increased survival, and proliferation. There is a strong association between chronic inflammatory con- At the molecular level, inflammation, transformation, survival, ditions and cancer specific to the organ. Epidemiological evi- and proliferation are regulated by nuclear factor κB(NF-κB), a dence points to a connection between inflammation and a pre- family of ubiquitously expressed transcription factors. NF-κBis disposition for the development of cancer, i.e., long-term inflam- activated by various inducers such as tobacco, alcohol, infections, mation leads to the development of dysplasia. Various factors are ionizing radiation, environmental pollutants, chemotherapeutic known to induce chronic inflammatory responses that further agents, and tumor necrosis factor-α (TNF-α). TNF-α is also one of cause cancer. These include bacterial, viral, and parasitic infec- the prime signals that induces apoptosis in many different types tions (e.g., Helicobacter pylori, Epstein-Barr virus, human immu- of cells. Whereas acute activation of NF-κB may be therapeutic, nodeficiency virus, flukes, schistosomes), chemical irritants (i.e., chronic activation may lead to the development of chronic in- tumor promoters, such as phorbol ester 12-O-tetradecanoyl-13- flammation, cancer, and other chronic diseases. NF-κB has been phorbol acetate, also known as phorbol myristate acetate), and associated with increased survival in many tumor cells; thus, its non-digestible particles (e.g., asbestos, silica) [25,26]. Epidemiol- inhibition could be a novel approach to breaking the vicious cycle ogical studies estimate that nearly 15% of the worldwide cancer of tumor cell proliferation. incidence is associated with microbial infection [27]. It is mechanistically proven that inflammation produces reactive oxygen species (ROS) and reactive nitrogen species (RNS). In par- What is NF-κB? ticular, ROS and RNS lead to oxidative damage and nitration of ! DNA bases, which increases the risk of DNA mutations and fur- NF-κB was first identified in 1986 by Sen and Baltimore [5]. In its ther leads to cancer [28]. The most thoroughly studied examples resting stage, this factor resides in the cytoplasm as a hetero- of inflammation and cancer are chronic inflammatory bowel dis- trimer consisting of p50, p65, and IκBα. The inhibitor IκBα masks ease and the increased risk of colorectal cancer, chronic gastritis the NF-κB nuclear localization domain and inhibits its DNA-bind- resulting from H. pylori infection and gastric adenocarcinoma, ing activity. In response to a large variety of stimuli, the IκB inhib- and chronic hepatitis and liver cancer. Chronic hepatitis B infec- itor is rapidly phosphorylated and degraded. This allows NF-κB tion leads to about a 10-fold increase in the risk of liver cancer nuclear translocation, DNA binding to specific recognition se- [29]. quences in promoters, and transcription of the target genes [6, Inflammation results in the recruitment of leukocytes secreting a 7]. The kinase that causes the phosphorylation of IκBα is called variety of proliferative cytokines and angiogenic factors to the IκBα kinase (IKK). IKKβ mediates the classic/canonical NF-κBacti- site of tissue insult. These cytokines are known to be required vation pathway, and IKKα mediates the non-canonical pathway. for proper wound healing, and stimulate epithelial cell prolifera- On activation, NF-κB induces the expression of more than 400 tion; however, if these are uncontrolled they could lead to dyspla- genes that have been shown to suppress apoptosis and induce sias and ultimately cancer. Tumor cells themselves also produce cellular transformation, proliferation, invasion, metastasis, che- various cytokines and chemokines that attract leukocytes, which moresistance, radioresistance, and inflammation [8,9]. The acti- in turn produce cytokines and chemokines that stimulate further vated form of NF-κB has been found to mediate different diseases, tumor cell proliferation. Paradoxically, cytokine deficiency (e.g., including cancer [8,10], atherosclerosis [11], myocardial infarc- GM‑CSF, IL-2 and IFNγ) can also lead to tumor development. Im- tion [12], diabetes [13] allergy [14,15], asthma [16], arthritis mune homeostasis consists of a succession of pro- and anti-in- [17], Crohnʼs disease [18], multiple sclerosis [19],