The development of cancer is a multiple step 天然物防癌機轉之研究. Cancer medicine e. Fifth Edition, Figure The spread of malignant tumours

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1 The development of cancer is a multiple step 天然物防癌機轉之研究 Cancer medicine e. Fifth Edition, Figure 12.1 The spread of malignant tumours 1

2 The nitrosamine NNK is produced in tobacco smoke from nicotine, a tobacco alkaloid (Hecht, 1985). This is an extremely potent carcinogen that may play a role in the induction of tobacco-related cancers in humans. The Search for the Origin of Cancer Inflammation and neoplastic progression Opposing effects of inflammation on cancer have been described, and at the risk of oversimplifying for the sake of clarity, it can be said that acute inflammation counteracts, while chronic inflammation promotes cancer development. Seminars in Cancer Biology, 2004 Updated central dogma, showing all the known paths of genetic information transfer. Under laboratory conditions, DNA can itself be translated into protein, but that circumstance apparently does not occur naturally. There is no known information flow beginning with protein, although the exact nature of prions has not been confirmed Initaition DNA damage /mutation Virus Radiation Chemical Promotion Preneoplastic lesion Malignant tumor Clincal cancer Chemical irritants : Phorbol ester Cytokine Chemokine Hormones Oxidative stress chronic Irritation, inflammation Progression Cancer metastasis Cancer Promoter 2

3 Chronic inflammation and Cancer Chronic inflammatory conditions associated with neoplasms 1858, Virchow observed that cancers frequently occurred at sites of chronic irritation. i Chronic inflammation, Virchow suggested, could lead to cellular proliferation and cancer development. This association is apparent under two circumstances: Arch Pathol Anat Klin Med., 1858 Chronic inflammation can predispose an individual to cancer, as demonstrated by the association between inflammatory bowel disease and colon cancer, chronic pancreatitis with pancreatic adenocarcinoma and hepatitis with hepatocellular carcinoma. Developing tumors induce a local and/or systemic chronic inflammatory atory environment associated with enhanced tumor development and metastasis. Nature, 2002; Cell, 2004 Table 1 Chronic inflammatory conditions associated with neoplasms Pathologic condition Associated neoplasm(s) Aetiologic agent Asbestosis, silicosis Mesothelioma, lung carcinoma Asbestos fibres, silica particles Bronchitis Lung carcinoma Silica, asbestos, smoking (nitrosamines, peroxides) Cystitis, bladder inflammation Bladder carcinoma Chronic indwelling, urinary catheters Gingivitis, lichen planus Oral squamous cell carcinoma Inflammatory bowel disease, Colorectal carcinoma Crohn s disease, chronic ulcerative colitis Lichen sclerosus Vulvar squamous cellcarcinoma Chronic pancreatitis, hereditary pancreatitis Pancreatic carcinoma Alcholism, mutation in trypsinogen gene on Ch. 7 Reflux oesophagitis, Barrett s Oesophageal carcinoma Gastric acids oesophagus Sialadenitis Salivary gland carcinoma Sjögren syndrome, MALT lymphoma Hashimoto s thyroiditis Skin inflammation Melanoma Ultraviolet light TRENDS in Immunology, 2005 Chronic inflammation and Cancer Chronic inflammation caused by biological, chemical, and physical agents is associated with an increased risk of cancer and other diseases. Archives of Biochemistry and Biophysics,

4 Cutting oil and dyes Skin and bladder cancer 4

5 The mechanisms for the involvement of inflammation in cancer development The mechanisms for the involvement of inflammation in cancer development Normal epithelium cell Recruitment of inflammatory cells Inflammation Virus, bacteria, UV, environmental oxadants etc ROS, TNFα, interleukin, Cytokines, COX-2, 5-LOX inos, MMPs, NF-κB, HIF-1α Stromal cell activation Angiogenesis Epithelial damage & apoptosis Reactive epithelial hyperproliferation Survival Proliferation Invasion Angiogenesis Metastasis Chemoresistance Radioresistance Dysplasia NATURE CLINICAL PRACTICE ONCOLOGY, 2005 Epithelium harboring mutations in genes regulating responses to trophic stimuli, apoptotic signalling, DNA damage, cell-cycle control Cancer Metastasis Mol Cancer Res., 2006 Key Molecular Players Linking Cancer to Inflammation Cancer chemoprevention Cancer development is a long-term process that appears to proceed by stepby-step carcinogenesis events that ultimately spread from one area of the body to other parts of the body during the late metastasis stage. TRENDS in Pharmacological Sciences, 2005 The strategy for control of cancer is based on the presumption that because cancer develops through a multi-step process, each step may be a prospective target for reversing or suppressing the process. Mutation Research, 2004 Mol Cancer Res.,

6 Cancer chemoprevention The mechanisms of cancer chemoprevention Chemoprevention is the use of a chemical substance of either natural or synthetic origin to prevent, hamper, arrest, or reverse a disease. In contrast to initiation, tumour promotion is considered to be a relatively lengthy and reversible process in which actively proliferating preneoplastic cells accumulate. Nature,, 2003 The term chemoprevention was coined by Michael Sporn in the mid-1970s. His work on retinoids against chemical carcinogenesis showed the time that cancer takes to develop in humans through the initiation, promotion, and progression stages. Fed. Proc., 1976 (DKFZ, German Cancer Research Center) Dietary substances with potential chemopreventive properties on CRC Phytochemicals are non-nutritive components in the plant-based diet ( phyto is from the Greek word meaning plant) that possess substantial anticarcinogenic and antimutagenic properties. Journal of Nutrition, 2004 Numerous cell-culture and animal model studies have been conducted to evaluate the ability of specific edible plants to prevent cancer. Nature, 2003 Phenolics Alkaloids Carotenoids Phytochemicals Nitrogen-containing compounds Terpenoids Organosulfur compounds Journal of Nutrition, 2004 Self-sufficiency in Growth Signals Evading Apoptosis Sustained Angiogenesis Apoptosis and Cancer Cancer Insensitivity to Anti-growth Signals Limitless Replicative Potential Tissue Invasion and Metastasis Hanahan, D. and Weinberg, R.A Cell. 100:57. Hanahan and Weinberg have proposed that normal cells must acquire six phenotypes to become malignant. One of these traits is resistance to apoptosis. In this model, the chronological order and mechanism by which these phenotypes are acquired may differ in each tumor. Genomic instability provides the driving force for acquiring new phenotypes. Thus, mutations in genomic caretaker systems such as p53 may increase the rate at which other alterations occur. 6

7 Apoptosis and Cellular Redox Environment Oxidants such as hydrogen peroxide can trigger apoptosis. Intracellular ROS generation by chemotherapeutics and ionizing radiation may be critical to induction of apoptosis by these agents. Depletion of glutathione pools occurs during apoptosis and GSH depletion can increase apoptosis, in some systems. Antioxidant enzymes and chemical antioxidants can protect against apoptosis. Oxidative damage to lipids and DNA is seen during apoptosis in some systems. ROS production can also attenuate apoptosis. Chandra, J. et al Free Rad. Biol. Med. 29:323. Buttke, T.M. and Sandstrom, P.A Free Rad. Res. 22:389. Neutrophil Eosinophil Macrophage Oxidative Stress and Cancer Oxidants Released by Inflammatory Cells - O 2 H 2 O 2 HOCl NO ONOO - NO 2 HO 1 O 2 The continuous production of oxidants at the site of chronic inflammation may cause cancer. Fitzpatrick, F.A., Int. Immunopharmacol. 1:1651. O'Byrne, K.J., and Dalgleish, A.G., Br. J. Cancer, 85:473. Kuper, H., et al J. Int. Med., 248:171. Shacter, E., and Weitzman, S.A., Oncology 16:217. Oxidative Stress, Inflammation and Cancer Oxidative Stress and Cancer Therapy Anti-Cancer Agents ROS are commonly thought to be toxic, resulting in oxidation of various cell constituents as DNA, lipids and proteins and consequently these oxidations may cause damage to the cellular mechinery leading to cell death as the ultimate consequence. Normal Oxidative stress + inflammation Doxorubicin Daunorubicin Mitomycin C Etoposide Cisplatin Adriamycin Arsenic trioxide Ionizing radiation Photodynamic therapy These anti-cancer agents depend exclusively or in part on the production of reactive oxygen species for cytotoxicity. Sensitivity of tumor cells to oxidative stress and/or apoptosis may affect treatment success. cancer Davis, W Pharmacol. Exp. Ther. 296:1. 7

8 Oxidative Stress, Apoptosis and Cancer: Some Models Carcinogenesis Antioxidants? FLAVONOIDS: FOCUS OF MUCH CURRENT NUTRITIONAL AND THERAPEUTIC INTEREST Chronic Oxidative Stress inflammation genetic disorder environment Cancer Therapy ROS-based Tumor Therapy Antioxidants? Genetic instability New phenotypes Apoptosis Growth Etc. Tumor contains apoptosisor oxidant-resistant cells NO YES Tumor Progression Tumor Regression Tumor Progression CARDIOPROTECTION Role for flavonoid-rich dietary components in reduction in risk of cardiovascular disease NEUROPROTECTION Anthocyanin-rich fruit associated with protection against age-related decline in cognitive function CHEMOPREVENTION Flavonoids: naturally occurring low molecular wt phenols consisting of 2 benzene rings linked via a heterocyclic pyrone or pyran ring -> patterns and substitutions comprising the sub-classes: Anthocyanin - berries Flavanone - citrus Flavanol - red wine teas chocolate fruit Flavonol - fruit Flavone - vegetables Hydroxycinnamates - most fruit & some vegetables 8