REVIEW Molecular mechanisms for chemoprevention of colorectal cancer by natural dietary compounds Min-Hsiung Pan 1à , Ching-Shu Lai 1 , Jia-Ching Wu 1 and Chi-Tang Ho 2 1 Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung, Taiwan 2 Department of Food Science, Rutgers University, New Brunswick, NJ, USA Received: August 30, 2010 Revised: September 26, 2010 Accepted: October 8, 2010 Colorectal cancer is one of the major causes of cancer-related mortality in both men and women worldwide. This review focuses on preventing the initiation and promotion of neoplastic growth in colorectal cancer, particularly with natural dietary compounds. Chemoprevention is defined as the use of natural dietary compounds and/or synthetic substances that can delay, prevent, or even reverse the development of adenomas, as well as the progression from adenoma to carcinoma. The molecular mechanisms of their chemo- preventive action are associated with the modulation of signaling cascades, gene expressions involved in the regulation of cell proliferation, differentiation, and apoptosis and the suppression of chronic inflammation, metastasis, and angiogenesis. Here, we summarize the currently known targets and signaling pathways whereby natural dietary compounds inter- fere with the development of colorectal cancer, and thus providing evidence for these substances in colonic cancer chemopreventive action. Keywords: Chemoprevention / Colorectal cancer / Flavonoids / Omega-3 fatty acids / Phenolic compounds 1 Introduction Colorectal cancer (CRC) is one of the major causes of cancer-related mortality in both men and women in most developed world [1]. The risk factors of CRC include age, family history, inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn’s disease, and environmental and dietary procarcinogens [2]. Epidemiological study showed that up to 40% patients with colitis developed colitis- associated CRC [3]. In colonic tumorigenesis, the inflam- matory cells contribute to the colitis by generating pro- inflammatory cytokines and diversing reactive oxygen species and RNS. Oxidative stress has the potential to affect a large array of carcinogenic pathway, because their targets including DNA, RNA, lipids, and proteins, involved in enhanced malignant transformation and proliferation of initiated cells (Fig. 1). Inflammation also promotes the development of cancer by creating an inflammatory micro- environment during tumor tissue formation. The inflam- matory and immuosuppressive cytokines and chemokines secreted from these cells not only promote proliferation, angiogenesis, invasion, and metastasis but also suppress the host’s immune system and facilitate tumor growth and development in CRC [4]. Many molecules such as LPS/Toll- like receptor 4/nuclear factor-kB (NF-kB) pathway, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; APC, adenomatous polyposis coli; CDK, cyclin-dependent kinases; CLA, conjugated linoleic acids; COX-2, cyclooxygen- ase-2; CRC, colorectal cancer; DHA, docosahexaenoic acid; DIM, 3,3 0 -diindolylmethane; DSS, dextran sulfate sodium; EGCG, epigallocatechin-3-gallate; EGFR, epidermal growth factor recep- tor; IBD, inflammatory bowel disease; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-jB, nuclear factor-kB; PI3K, phos- phatidylinositol-3 kinase; TNBS, 2,4,6-trinitrobenzenesulfonic acid; TNFa, tumor necrosis factor a à Additional corresponding author: Dr. Min-Hsiung Pan E-mail: mhpan@mail.nkmu.edu.tw Correspondence: Dr. Chi-Tang Ho, Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, New Jersey 08901-8520, USA E-mail: ho@aesop.rutgers.edu Fax: 11-732-932-6776 & 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com 32 Mol. Nutr. Food Res. 2011, 55, 32–45 DOI 10.1002/mnfr.201000412