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Anti-Inflammatory Life Style for Prevention and Treatment of Cancer: Facts and Fiction

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Anti-Inflammatory Life Style for Prevention and Treatment of Cancer: Facts and Fiction Bharat B. Aggarwal, Ph.D. Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of
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Anti-Inflammatory Life Style for Prevention and Treatment of Cancer: Facts and Fiction Bharat B. Aggarwal, Ph.D. Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, U.S.A. The Society for Integrative ncology Host; Laura Vecchio Albany, New York (1SI) (Webinar on Tuesday; August 13 th, 12:00-1:00 PM) Several age-related chronic diseases such as metabolic syndrome, cardiovascular disease, and neurodegenerative disease have an inflammatory component January 11th, 2013 A yin-yang symbol superimposed on a scanning electron micrograph of a mouse tissue alveolar macrophage. Macrophages are immune cells that mediate inflammation, but they often play protective roles as well. Sick Societies: Responding to the global challenge of chronic disease David Stuckler (Author), Karen Siegel (Author) (xford Press) Sept 21 st, 2012 Inflammation, Lifestyle and Chronic Diseases: The Silent Link Bharat B. Aggarwal, Ph.D. (Editor), Sunil Krishnan, M.D. (Editor), Sushovan Guha, M.D. (Editor) (Francis and Taylor) Signalling pathways of the TNF superfamily: a double-edged sword. Aggarwal BB. Nature Reviews Immunology 2003 Sep;3(9): Historical perspectives on tumor necrosis factor and its superfamily: twenty-five years later, a golden journey. Aggarwal BB, Gupta SC, Kim JH. Blood Jan 19;119(3): Aggarwal-638 TIME Feb. 23, 2004 TIME Feb. 23, 2004 Controlled Inflammation/Flame/Fire Uncontrolled Life style Carcinogens/Risk factors Cancer Is a Preventable Disease That Requires Major Changes in Life Style Tobacco Diet besity Infections E. Pollution Genes & Radiations HK Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009 Reduce your risk of cancer by 30 to 40% by adopting healthier eating habits. Visit: Potential Sources of Inflammation Ultraviolet radiation Alcoholic beverages Inflammation Environmental pollutants Industrial pollutant, Diesel, Acid rain Food Factors Grill, Fried, red meat Stress ph, hypoxia, heavy metals, chemotherapy Cigarette smoke Bacteria Helicobacter pylori Salmonella typhi Chlamydia pneumoniae Streptococcus bovis Escherichia coli Viruses Herpes simplex virus 8, Hepatitis viruses, HPVs,HIV, EBV Working Hypothesis: Dysregulated chronic inflammation caused by life style factors mediate chronic diseases including cancer! Inflammation and cancer Redness, swelling, heat and pain Rudolf Virchow ( ; in 1850) His Pathology laboratory in Wurzburg, Germany Linked Inflammation with atherosclerosis, rheumatoid arthritis, multiple sclerosis, cancer, asthma, Alzheimer s From Heidland A et al, History of Nephrology, Inflammation is itis Arthritis is inflammation of the joints Bronchitis. Bronchus Sinusitis Sinus Gastritis. Stomach Esophagitis.. Esophagus Pancreatitis.. Pancreas Meningitis Brain Rhinitis Rhina Gingivitis Gum Adenitis Adrenalitis Allergic rhinitis Appendicitis Arachnoiditis Arteritis Arthritis Blepharitis Bronchiolitis Bronchitis Bursitis Capsulitis Carditis Cellulitis Cerebellitis Cerebritis Cervicitis Cheilitis Cholecystitis Chondritis Chorditis Choroiditis Colitis Conjunctivitis Cystitis Dermatitis Dermatomyositis Diverticulitis Duodenitis Pancreatitis Panophthalmitis Pansinusitis Paracolpitis Paraglottitis Paradenitis Parahepatitis Parametritis Paranephritis Parasalpingitis Parodontitis Parotitis Periadenitis Periangitis Periarteritis Periarthritis Pericarditis Periodontitis Peritonitis Pharyngitis Phlebitis Pleuritis Pneumonitis Poikilodermatomyositis Proctitis Pyelonephritis Retinitis Rhinitis Rheumatoid arthritis Salpingitis Salpingo-oophoritis Sialoadenitis Sinusitis Sphenoiditis Splenitis Spondylitis Stomatitis Syndesmitis Synovitis Tendonitis Temporal arteritis Tenosynovitis Thrombophlebitis Thyroiditis Typlitis Tonsillitis Urethritis Uveitis Vaginitis Valvulitis Vulvitis Vulvovaginitis Encephalitis Endocarditis Endotracheitis Endometritis Enteritis Enterocolitis Epididymitis Epididymo-orchitis Fibrositis Epiglottiditis Epiphysitis Episcleritis Esophagitis Ethmoiditis Fascitis Fibromyositis Folliculitis Funiculitis Gastritis Gastroenteritis Gingivitis Glossitis Glottitis Glomerulonephritis Hepatitis Hidradenitis Ileitis Iritis Iridocyclitis JejunitisKeratitis Keratodermatitis Laminitis Laryngitis Lymphadenitis Lymphangitis Mastitis Mastoiditis Meningitis Meningomyelitis Myelitis Myeloencephalitis Myocarditis Myositis Myringitis Nephritis Neuritis Neuroretinitis mphalitis nychitis ophoritis ophorosalpingitis phthalmitis rchitis steochondritis steitis titis ptic neuritis steoarthritis Inflammation-mediated diseases Inflammation as a risk factor for most cancers Inducer Inflammation Cancers % predisposed progress to cancer Tobacco smoke Bronchitis Lung Cancer Helicobacter pylori Gastritis Gastric Cancer 1-3 Human papilloma virus Cervicitis Cervical cancer 1 Hepatitis B & C virus Hepatitis HCC 10 Bacteria, GBS Cholecystitis Gall bladder cancer 1 2% Gram- uropathogens Cystitis Bladder cancer 1 Tobacco, genetics Pancreatitis Pancreatic cancer 10% GA, alcohol, tobacco Esophagitis Esophageal cancer 15 Asbestos fibers Asbestosis Mesothelioma Epstein-Barr virus Mononucleosis Burkitt s lymphoma 1 Hodgkin s disease Gut pathogens IBD Colorectal cancer 1* Ultraviolet light Sunburn Melanoma 9% Infections, STD PIA Prostate cancer? GA, gastric acid; GBS, gall bladder stones; HCC, hepatocellular carcinoma; STD, sexually transmitted diseases; PIA, prostate inflammatory atrophy. From: Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology, 72, 2006, Hypothesis! NF- B activation is a major mediator of inflammation in most chronic diseases (including cancer) & inhibition of NF- B can prevent/delay the onset of the chronic diseases! NF- B -regulated genes Kumar A, Takada Y, Boriek AM, Aggarwal BB. Journal of Molecular Medicine 2004;82: Inflammatory networking in cancer Survival & Chemoresistance: c-flip, Bcl-x L IAP-1, IAP-2, XIAP, survivin Proliferation: Cyclin D1, 5-LX, CX-2, IL-6 TNF NF-kB IL-6 Bone loss RANKL, IL-1, TNF Invasion and metastasis Chemokines STAT3 Angiogenesis VEGF Aggarwal BB, et al. Inflammation and cancer: How hot is the link? Biochemical Pharmacology. 2006 Regulation of Inflammatory Network Chemo NF-kB..nib..mab Radiation Constitutive activation of NF- B has been linked with most cancers Esophageal cancer Laryngeal cancer Pharyngeal cancer Pancreatic cancer Renal carcinoma Colon cancer Head and neck SCC Lung cancer Bladder cancer Acute Myelogenous leukemia Tobacco-linked cancers Thyroid cancer Hodgkin s disease Liver cancer Non-Hodgkin s lymphoma B cell lymphoma Carcinogens NF- B Carcinogens Breast cancer varian cancer T cell lymphoma Prostate cancer Mantle cell lymphoma Multiple myeloma Viral cancers UV light Acute lymphoblastic leukemia Adult T cell leukemia Cervical cancer Nasopharyngeal carcinoma Melanoma Shishodia and Aggarwal, Biochemical Pharmacology, 2004 NF-κB addiction and its role in cancer: ne size does not fit all Chaturvedi MM, Sung B, Yadav VR, Kannappan R, and Aggarwal BB NCGENE (2011 Apr 7;30(14): ) Cross Talk between NF- B and other transcription factors Chaturvedi etal, 2010 Role of inflammation in tumorigenesis NF- B DNA damage ncogenes Bcl-xl Bcl-2 Survivin C-FLIP ciap-1 ciap-2 XIAP Cyclin D1 C-myc TNF IL-1 IL-6 CX2 MMP-9 upa ICAM-1 ELAM-1 VCAM-1 VEGF CXCR4 TWIST Transformation Tumor suppression Normal cell Transformation Survival Proliferation Invasion Angiogenesis Metastasis Years 10 Years Inflammation Aggarwal etal, CCR, 2010 NF-kappa B activation has been linked to most major diseases Kumar A, Takada Y, Boriek AM, Aggarwal BB. Journal of Molecular Medicine 2004;82: Cigarette Smoke Activates Nuclear Factor- B and Induces Cyclooxygenase-2 Anto R. J., Mukhopadhyay A., Gairola C. G. and Aggarwal B. B., Carcinogenesis, 23, 1511, 2002 Cigarette smoke-induced NF- B activation is persistent Cigarette smoke t (h) NF- B Fold Shishodia S, and Aggarwal BB. Cancer Research. 2004;64: NF- B expression in the pathogenesis of lung cancer AAH Normal Epithelium Hyperplasia Squamous Metaplasia Moderate Dysplasia Carcinoma In Situ Tang et al, 2006 besity and Cancer F5 Esophageal cancer Multiple myeloma Colon cancer Renal cancer Non-Hodgkin s lymphoma Cervical cancer Pancreatic cancer besity 14% 20% Gastric cancer Gall bladder cancer varian cancer Rectal cancer Breast cancer Uterine cancer Endometrial cancer Liver cancer Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009 NF- B NF- B: the enemy within. Aggarwal BB. Cancer Cell Sep;6(3): NF- B : a friend or a foe in cancer? Shishodia S, Aggarwal BB. Biochem Pharmacol. 2004;68: NF-κB in Cancer: A Matter of Life and Death. Aggarwal BB, Sung B. Cancer Discovery Nov;1(6): NF- B Characterization of receptors for human TNF and their regulation by IFN-g. Aggarwal BB, Eessalu TE, Hass PE. Nature Dec Jan 1;318(6047): T-helper-1-cell cytokines (TNF-a and IFN-g) drive cancer into senescence. Braumüller H,.., Röcken M. Nature Feb 21;494(7437): Impaired interferon signaling is a common immune defect in human cancer. Critchley-Thorne RJ,.., Lee PP. Proc Natl Acad Sci U S A Jun 2;106(22): Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D. Nature May 9;497(7448):211-6. NF- B Hypothalamic inflammation verweight Glucose intolerance Hypertension Aging IKKb/NF-kB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Li, J.,.. Nature Cell Biol. 14, (2012). Hypothalamic IKKb/NF-kB and ER stress link overnutrition to energy imbalance and obesity. Zhang, X. et al. Cell 135, (2008). Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Purkayastha,S.etal. PNAS 108, (2011). Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-b and NF-kB. Purkayastha,S.,..Nature Med. 17, (2011). NF- B NF- B: the enemy within. Aggarwal BB. Cancer Cell Sep;6(3): NF- B : a friend or a foe in cancer? Shishodia S, Aggarwal BB. Biochem Pharmacol. 2004;68: NF-κB in Cancer: A Matter of Life and Death. Aggarwal BB, Sung B. Cancer Discovery Nov;1(6): NF- B: a pivotal transcription factor in chronic inflammatory diseases. Barnes PJ, Karin M. New England Journal of Medicine Apr 10;336(15): NF-kB in cancer development and progression Karin M. Nature May 25;441(7092):431-6. NF- B & Cancer NFKBIA deletion in glioblastomas. Bredel, 2011; N Engl J Med Feb 17;364(7): Monoallelic deletion of NFKBIA in glioblastoma: when less is more. Rinkenbaugh AL, Baldwin AS.Cancer Cell Feb 15;19(2): ncogenic EGFR signaling activates an mtrc2-nf-κb pathway that promotes chemotherapy resistance. Tanaka K,. Cancer Discov Nov;1(6): FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Bivona TG,... Nature Mar 24;471(7339): Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Meylan E,.Jacks T. Nature Nov 5;462(7269):104-7. Working Hypothesis Stress NF-kappaB Inflammation Cancer Nearly 43% of patients with ulcerative colitis develop colorectal cancer after Ekbom A, 1998 Inflammatory bowel disease: a survey of the epidemiology in Asia. Goh K, Xiao SD. Journal of Digestive Diseases Feb;10(1):1-6. Prevalence of rates of Ulcerative Colitis: JAPAN 7.9 per 100,000 INDIA 44.3 per 100,000 USA per 100,000 Migrant studies of South Asians in the UK, where second-generation immigrants have assumed incidence rates as high as the indigenous whites and Asian Jews who develop high incidence rates comparable to Jews from Europe or North America in Israel point to the role of environmental factors. Studies have suggested a change in diet to a more Westernized one may underlie this epidemiological change in the Asian population. It is likely that there are racial groups amongst Asians who are more susceptible to IBD and who will demonstrate a higher frequency of IBD when exposed to putative environmental factors. A Fire Extinguisher! How to suppress NF- B activation safely? Wonders of Modern Medicine Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Fojo T, Parkinson DR. Clinical Cancer Research Dec 15;16(24): Medical ncology Branch, Center for Cancer Research, Bethesda, Maryland, USA. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Coussens LM, Zitvogel L, Palucka AK. Science Jan 18;339(6117): Neutralizing tumor-promoting chronic inflammation: a magic bullet? Coussens LM, Zitvogel L, Palucka AK. Science Jan 18;339(6117): Steroids NSAID Celebrex Metformin Statins Natural Products & Traditional Medicine Aspirin (Salicylic acid; bark and leaves of willow tree) Steroids (Fenugreek; Diosgenin) Statins (Aspergillus terreus) Metformin ( Galega officinalis; goat's rue ) The Greek physician Hippocrates wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers. Fruits and vegetables are natural sources of salicylic acid, particularly blackberries, blueberries, cantaloupes, dates, raisins, guavas, apricots, green pepper, olives, tomatoes, radish, mushrooms and chicory. Some herbs and spices contain quite high amounts. f the legumes, seeds, nuts, and cereals, only almonds, water chestnuts and peanuts have significant amounts. Galega name derives from gale (milk) and ega (to bring on), as Galega has been used as a galactogogue in small domestic animals (hence the name Goat's rue ). Carl Djerassi worked on a new synthesis of cortisone based on diosgenin, a steroid sapogenin derived from a Mexican wild yam. Prevention by Aspirin Myocardial infarction Cancer Aspirin Ischemic stroke Haemorrhagic stroke Aspirin ups risk of cancer survey Women who take aspirin regularly for 20 years have an increased chance of developing pancreatic cancer, according to a survey of 90,000 females. Scientists studied thousands of American women, finding that those who took two or more tablets each week for two decades had a 58% increased chance of developing the disease. The risk of developing pancreatic cancer increased as the dose got bigger up to 86% higher for those who took the drug twice a day. Aspirin has been hailed as a wonder drug and is commonly recommended as a preventative treatment for heart disease. It has also been suggested as a preventative drug against Alzheimer's disease and can prevent deep vein thrombosis during long haul flights. The researchers, based at the Brigham and Women's Hospital and Harvard Medical School in Boston, warned in their study that doctors and patients must balance the benefits of aspirin with the risks suggested by the new study. The scientists studied nearly 90,000 women. Among them, 34% were defined as regular users, taking two or more 325mg aspirin tablets per week. The regular users, over the next two decades, were found to be 58% more likely to develop cancer of the pancreas. Those who took two tablets a day for 20 years were 86% more likely to get the cancer, said the report, published in the Journal of the National Cancer Institute. Read more: Follow on Twitter DailyMail on Facebook TNF Blockers ( $20 billion/year) Crohn s Disease Rheumatoid arthritis Psoriasis FDA approved uses of TNF blockers Ankylosing spondylitis Ulcerative colitis Juvenile idiopathic arthritis Selected FDA approved TNF blockers Drug Mechanism Disease Infliximab mabs RA, PA, psoriasis, ALS, ulcerative colitis, Crohn's disease Etanercept RD RA, PA, psoriasis, ALS, juvenile RA Adalimumab mabs RA, PA, psoriasis, ALS, juvenile RA, Crohn's disease Certolizumab mabs RA, Crohn's disease Golimumab mabs RA, PA, AS Aggarwal et al., 2011, Autoimmune diseases Ankylosing spondylitis Multiple sclerosis Eczema Hidradenitis suppurativa Inflammatory bowel disease Atopic dermatitis Rheumatoid arthritis Psoriasis Sarcoidosis Scleroderma Systemic lupus erythematosus Cardiovascular diseases Atherosclerosis Myocardial infarction TNF-α Neurologic diseases Alzheimer's disease Epilepsy Bipolar disorder Parkinson's disease Depression steoporosis Cancer Non-alcoholic fatty liver disease Metabolic diseases besity Diabetes, type 2 Pulmonary diseases Asthma Chronic obstructive pulmonary disease Various diseases that have been closely linked to TNF-α and members of its family. Aggarwal et al., 2011, Blood TNF blockade: an inflammatory issue Aggarwal BB, Shishodia S, Takada Y, Jackson- Bernitsas D, Ahn KS, Sethi G, Ichikawa H. Ernst Schering Res Found Workshop. 2006;(56): Review. TNF Blockers ( $20 billion/year) Lymphoma Infections T cell Non-Hodgkins Lymphoma Black label warning Develop resistance Cutaneous T Cell lymphoma Injectable only Sezary syndrome Deepak, 2012; Askling, 2005a, 2005b; Siegel, 2009; Herrinton, 2011; Parakkal, 2011; Adams, 2004; Dalle, 2005; Michot, 2009; Dauendorffer, 2007; Lourari, 2009; Schmidt, 2009; Mackey, 2007 Evidence that curcumin is an orally bioavailable TNF-a blocker in human TNF- (pg/ml) Placebo N=21 Serum TNF- (pg/ml) N=23 Pre Post Curcumin (150 mgx2 daily) 8 wks Usharani, 2008 Regulation of production and action of TNF by curcumin .Sloan School of Management at M.I.T. and the Harvard Business School has created Pharmer s Market, however, we need a Farmer s Market New York Times, November, 2009 Farmer s Market Fruits Spices & condiments Vegetables Cereals Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009 Farmer s Market Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009 Farmer s Market Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009 Farmer s Market Anand P, Harikumar K and Aggarwal BB; Pharmaceutical Research, 2009 Hippocrates proclaimed ~2500 years ago Let food be thy medicine and medicine be thy food Sept 21 st, Antiinflammatory life style Spices Fruits & Vegetables Asian ginger (1) (Alpinia galanga) Fennel (2) (Foeniculum vulgare) Sesame seed (3) (Sesamum indicum) Turmeric (4) (Curcuma longa) Cloves (5) (Eugenia caryophyllu) Cauliflower (1) (Brassica oleracea) Mullberry (2) (Morus nigra) Artichoke (3) (Cynara cardunculus) Grapes (4) (Vitis vinifera) Soybean (5) (Glycine max) Red chili (6) (Capsicum annum ) Fenugreek (7) (Trigonella foenum graecum) Poppy seed (8) (Papaver somniferum) Gamboge (9) (Garcinia hanburyi) nion (10) (Allium cepa) Traditional Chinese Medicine nion seed (11) (Nigella sativa) Holy basil (12) (cimum sanctum) Pomegranate (13) (Punica granatum) Lacquer tree (1) (Rhus verniciflua) Goldenseal (2) (Hydrastis canadensis) God of thunder vine (3) (Tripterygium wilfordii) Smoke tree (4) (Cotinus coggygria) Ayurvedic Medicine Evodia (5) (Evodia rutaecarpa) Song gen (6) (Phellinus linteus) Magnolia (7) (Magnolia officinalis) Aloe (1) (Aloe vera) Veldt-grape (2) (Cissus quadrangularis) Picroliv (3) (Picrorhiza kurroa) Himalayan fir (4) (Abies webbiana) Chitrak (5) (Plumbago zeylanica) thers Boswellia (7) (Boswellia serrata) Beauty berry (7) Pink trumpet tree (8) (Callicarpa macrophylla) (Tabebuia avellanedae) Bloodroot (9) (Sanguinaria canadensis) Guggulu (10) (Commiphora mukul) Cashew nut (1) Horse chestnut (2) Palm (3) Elephant's foot (4) Hop (5) (Anacardium occidentale) (Aesculus hippocastanum) (Elaeis guineensis) (Elephantopus scaber Linn) (Humulus Iupulus L.) False pepper (11) (Embelia ribes) Rohitukine (12) (Dysoxylum binectariferu m) Ashwagandha (13) Indigo (14) Pinecone ginger (15) (Withania somnifera) (Polygonum tinctorium) (Zingiber zerumbet) Ginger lily (6) (Hedychium coronarium) Cork bush (7) (Mundulea sericea) Tropical rose mallow (8) leander (9) (Hibiscus vitifolius) (Nerium oleander) H H H H 3 C HC N H H 1 -Actoxychavicol acetate (1) Capsaicin (6) H H H H H H 3 C H H H H H H CH 3 H Anethole (2) Sesamin (3) H H H H H 3 C Spices H CH 3 H H 3 C H H 3 C H H 3 C CH3 N CH 3 H H Diosgenin (7) Noscapine (8) H CH Ayurvedic Medicine N H H H H Cinnamoyl CH H N
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