Presentation on theme: "Innate glutathione production Glutathione levels are the highest for about six hours after each meal. Our lowest level of glutathione is in the morning."— Presentation transcript:
Innate glutathione production Glutathione levels are the highest for about six hours after each meal. Our lowest level of glutathione is in the morning before our first meal. While healthy children and young adults tend to have sufficient glutathione, glutathione production decreases as we age. Once we reach the age of 45, production declines precipitously. Add to this, glutathione depleting activities, and our glutathione stores can become seriously depleted 1
Stress-induced glutathione depletion Chronic neuroendocrine stress leads to the elevation of cortisol, norepinephrine and epinephrine and increased metabolic rate - which is frequently accompanied by oxidative damage and depleted antioxidants High levels of stress hormones promote lipid storage as organ fat rather than subcutaneous fatty tissue. Organ adipocytes secrete proinflammatory cytokines, which increase oxidation, leading to a depletion of antioxidants, especially glutathione, and ultimately to cell injury, organ damage and disease. 3 Djordjevic J, et al. Cell Mol Neurobiol. 2010;30(5):693. Abraham NG, et al. Ann N Y Acad Sci Oct;1113:256-75
Cell signaling: Psychological Stress 4
Stress & Cancer Progression and epidemiological studies over the last 30 years have identified psychosocial factors especially stress, chronic depression and feelings of isolation as risk factors for cancer progression. Clinical and epidemiological studies over the last 30 years have identified psychosocial factors especially stress, chronic depression and feelings of isolation as risk factors for cancer progression. Chronicity of negative affect, as manifested by depressed mood or hopelessness/pessimism, appears to have stronger relationships with outcomes than do stressful events. Chronicity of negative affect, as manifested by depressed mood or hopelessness/pessimism, appears to have stronger relationships with outcomes than do stressful events. This suggests that sustained activation of negative affective pathways may provide the strongest links to cancer progression. This suggests that sustained activation of negative affective pathways may provide the strongest links to cancer progression. 5 Moreno-Smith M. et al. Future Oncol Dec;6(12):
Stress, Depression and Renal cell carcinoma 217 participants with newly diagnosed metastatic RCC (MD Anderson Cancer Center) with life expectancy of greater than 4 months, good performance status (<2) and no major concurrent diseases. Baseline: Depression questionnaires, Salivary cortisol, blood sample for genomic analysis The following factors were associated with survival time: CES-D scores SF-36 PCS scores cortisol slope risk category 6 Cohen L. PLoS One. 2012;7(8):e42324.
Stress, Depression and RCC 7 Gene Ontology analyses identified upregulation of genes involved in inflammation, immune response, and negative regulation of programmed cell death (all p<.0001) and down- regulation of genes involved in cell trafficking, adhesion, oxygen transport, and hemostasis (all p<.05).
Cancer Determinant: Signal transduction, or extrinsic carcinogenesis 8 Devita VT, et al. Hellman and Rosenberg’s Cancer: Principles & Practice of Oncology, 9 th ed, 2011: Upregulated signal transduction results in abnormal rate of gene transcription which will ultimately destabilize chromosomes leading to further methylation changes and malignant transformation.
Sensitivity of signal transduction Cells are exquisitely sensitive to ligands (picomolar to nanomolar range) Very few receptors are required to transmit a signal i.e. only 10 receptors on a T-cell need to be stimulated to activate a maximal response Given the small number of receptors involved in most actions, the signals are amplified intracellularly. Relatively small changes in the tissue mileau can profoundly affect signal transduction. Hormones, interleukins and prostaglandins are some of the most influential of these ligands. 9
NF-kB, IL-6 and breast cancer stem cells Malignant stem cells are the result of one stable cell type changing into another stable cell type without any modifications to the genetic sequence of the cell – an epigenetic phenomenon. Inflammatory response activates NF-kB NF-kB activation decreases mRNA (Let-7 mRNA) thereby releasing repression of IL-6 IL-6 signaling pathways are induced leading to the intrinsic self-renewal capacity characteristic of breast cancer stem cells 12 Shostak K and Chariot A.. Breast Cancer Research. 2011;13(4):214.
IL-6: Breast Cancer survival 13 Bachelot T, et al. Br J Cancer Jun 2;88(11): IL-6 < 55 pg/mL IL-6 > 55 pg/mL
CRP: Prostate cancer survival 14 Beer TM, et al. Cancer Jun;112(11):
Plant food and NF-kB signaling 15 Anand P. et al. Pharmacetuical Research, 2008;25(9):2097.
NFkB inhibition: anthocyanidins Anthocyanins isolated from bilberries and black currants (Medox) efficiently suppressed LPS- induced activation of NF-kappaB in cultured monocytes. Anthocyanins isolated from bilberries and black currants (Medox) efficiently suppressed LPS- induced activation of NF-kappaB in cultured monocytes. Parallel-designed, placebo-controlled clinical trial (n = 120 men and women aged y) (23) Parallel-designed, placebo-controlled clinical trial (n = 120 men and women aged y) (23) Intervention consisted of Medox, 300 mg/d for 3 wk Intervention consisted of Medox, 300 mg/d for 3 wk Decreases in the NF-kappaB-controlled pro-inflammatory chemokines and IFNalpha (an inducer of NF-kappaB activation) in the Medox group Decreases in the NF-kappaB-controlled pro-inflammatory chemokines and IFNalpha (an inducer of NF-kappaB activation) in the Medox group 45% and 40% respective decreases from baseline vs. placebo group with 20% and 15% decreases from baseline) (P < 0.050) 45% and 40% respective decreases from baseline vs. placebo group with 20% and 15% decreases from baseline) (P < 0.050) 16 Karlsen A et al. J Nutr Aug;137(8):1951-4
Walnuts and VEGF The aim of the present study was to examine the effect of dietary walnuts on colorectal cancer in vivo and to comparatively evaluate their efficacy in relation to flaxseed oil. METHODS: HT-29 human colon cancer cells were injected in 6-wk-old female nude mice. After a 1-wk acclimation period, mice (n = 48) were randomized to diets containing ~ 19% of total energy from walnuts, flaxseed oil, or corn oil (control) and were subsequently studied for 25 d. RESULTS: Tumor growth rate was significantly slower in walnut-fed and flaxseed-fed mice compared with corn oil-fed animals (P < 0.05) by 27% and 43%, respectively. Accordingly, final tumor weight was reduced by 33% and 44%, respectively (P < 0.05 versus control); the differences between walnut and flaxseed diets did not reach significance. Dietary walnuts significantly decreased angiogenesis (CD34 staining; P = versus control), whereas this effect did not reach significance in the flaxseed oil group (P = versus control). 17 Nagel JM, et al. Nutrition (l):67-75.
IL-6: Immune shift IL-6, also known as B cell stimulatory factor-2 (BSF- 2), is a terminal differentiation factor for B cells that is produced by monocytes and lymphocytes as part of Th2 immune activation. Shifting immune activity away from Th2 and towards Th1 will decrease PBMC production of IL-6. Increase Th1 with (examples): PSK from Coriolus (Trametes) versicolor Melatonin Probiotics Lower Th2 by eliminating dietary allergens 18 Giannoulia-Karantana A, et al. Neuroimmunomodulation. 2006;13(3): Carrillo-Vico A, et al. FASEB J Mar;18(3):537-9.
Plant flavonoids and anti-inflammatory Nrf-2 The transcription factor Nrf2 is kept sequestered in cytoplasm as an inactive complex with its cytosolic repressor Keap-1. Chemopreventive phytochemicals activate diverse upstream kinases, which in turn stimulate dissociation of Nrf2 from Keap-1. Once released from Keap-1 repression, Nrf2 translocates to nucleus, forms heterodimer with small Maf protein, and binds to ARE/EpRE sequences located in the promoter region of genes encoding antioxidant and detoxifying enzymes. 19 Surh Y-J. Journal Nutr. 2005;135: 2993S–3001S.
Flavonoids and colon cancer Controlled trial of 87 patients 36 patients with resected colon cancer 51 patients after polypectomy Entire group was divided into 2 groups: one group was treated with a flavonoid mixture (daily standard dose 20 mg apigenin and 20 mg epigallocathechin-gallate, n = 31) and compared with a matched control group (n = 56). Both groups were observed for 3-4 years by surveillance colonoscopy and by questionnaire. Among the flavonoid-treated patients with resected colon cancer (n = 14), there was no cancer recurrence and one adenoma developed. The cancer recurrence rate of the 15 matched untreated controls was 20% (3 of 15) and adenomas evolved in 4 of those patients (27%). The combined recurrence rate for neoplasia was 7% (1 of 14) in the treated patients and 47% (7 of 15) in the controls (P = 0.027). 20 H. Hoensch, et al. World J Gastroenterol Apr 14;14(14):
Green tea Male patients who consumed over 10 cups of green tea daily died 3.6 years later than did their male counterparts who drank less than 3 cups daily. Female patients who consumed over 10 cups of green tea daily died 7.8 years later than did their female counterparts who drank less than 3 cups daily. In addition, the age at onset of cancer was 3.0 years later in men and 8.7 years later among women who drank over 10 cups of green tea daily than those drinking less than 3 cups of green tea daily. The difference between male and females was explained by the higher tobacco use by men. Finally, in an extension of this same study, the researchers determined that women who drank over 10 cups of green tea daily showed a lower relative risk of cancers of the lung, colon, and liver. 21 Imai K, et al. Prev Med,1997 Nov-Dec;26(6):769-75
Green tea and Breast cancer 22 Histologically confirmed invasive breast carcinoma n = 472 Japanese premenopausal women Stages I – IIIFollowed for 7 years post surgery P < 0.05 Ave. = 2 cups/d Ave. = 8 cups/d Nakachi et al, Jpn J Cancer Res, 1998 Mar;89(3):
Green tea and breast cancer 23 A prospective cohort study conducted over a 9-year period from 1990 to In 1990, 1160 new surgical cases of invasive breast cancer in female patients at a Japanese cancer center were enrolled in the study. During 5264 person-years of follow-up (average 4.5 years per subject), 133 subjects (12%) experienced recurrence. Risk of Recurrence with consumption of > 3 cups Green Tea/day PatientsHR95% Confidence Interval All stages Stage I Stage III and IVNo change--- Average consumption = 5 cups/d Inoue, et al, Cancer Lett, 2001 Jun 26;167(2):
Lycopene and Prostate cancer Demonstrated effectiveness in pre-clinical studies The prostate gland concentrates lycopene Highest serum levels of lycopene compared to the lowest is associated with an 83% reduction in PCa. Majority of clinical studies in men with PCa show improvements in PSA kinetics and disease stabilization. 24 Trottier G. et al. Nat Rev Urol Jan; 7(1);21-30 Lu QY, et al. Cancer Epidemiol Biomarkers Prev Jul; 10(7):
Lycopene 26 men with newly diagnosed localized PCa. Randomized to 30mg lycopene or no supplement prior to radical prostatectomy. Lycopene group: Smaller tumors: 84% vs. 45% with tumors <4mL Clean margins: 73% vs. 18% PIN: 67% vs. 100% PSA: -18% vs. +14% 41 men with Gleason score 6 and rising PSA Treated with 5mg lycopene BID x 1y PSA velocity decreased in 71% PSA slope was negative in 21% 25 Kucuk O. et al. Exp. Biol. Med (Maywood) Nov;227(10): Zhang X. et al. Chin Med J (Engl) Aug;123(16):
Flaxseed 25 men with PCa treated with low fat diet + 30g flaxseeds for an average of 34d prior to prostatectomy. Matched to historic controls In men with Gleason < 6, PSA reduced (7.1 vs. 6.4 ng/mL) Prostate cancer cells had significantly decreased proliferation and increased apoptosis compared to controls. Follow-up study with 161 men Randomized to Flaxseed, Flaxseed+low fat diet or usual diet Cancer cell proliferation significantly lower for flaxseed (51%) and flaxseed + low fat diet (54%) compared to controls. 26 Demark-Wahnefried W. et al. Urology Jul;58(1):47-52 Denmark-Wahnefried W. et al. Cancer Epid. Biomarkers Prev Dec;17(12):
27 Deadly Signaling Trio: Obesity, Insulin Resistance and Inflammation IR arises from either increased dietary glucose and/or defects in the insulin signaling pathway Cancer cells are saturated with insulin receptors Insulin is a direct growth factor in cancer cells. When insulin is elevated, so is IGF-1, another tumorigenic growth factor. 27 Van Kruijsdijk RC, et al. Cancer Epidemiol Biomarkers Prev. 2009;18:
Obesity is a carcinogenic state 28 Van Kruijsdijk RC, et al. Cancer Epidemiol Biomarkers Prev. 2009;18:
Weight Being overweight or obese is responsible for one in six cancer deaths in the United States Weight, weight gain, and obesity account for approximately 20% of all cancer cases. Excess weight increases the chance of dying of prostate cancer by 34% Being overweight more than doubles the risk of dying of breast cancer According to the WCRF, the strongest evidence exists for an association of obesity with the following cancer types: endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, renal, leukemia, non-Hodgkin’s lymphoma, multiple myeloma, malignant melanoma, and thyroid tumors 29 Wolin et al. The Oncologist. 2010;15:556–565 Magheli et al. Urology. 2008;72(6): WCRF, Food Nutr Phys Activ Prev Cancer, AICR, 2 nd ed. 2007
30 Tumor Cell Proliferation Tumor Growth Tumor Sensitivity to Treatment Visceral Obesity Insulin Resistance Increased IGF-1/ Insulin Signaling (IGF-1, IR-IGF-1R Hybrid R) Inactivity Cancer Recurrence Cancer Survival Adult Energy Imbalance Excess Caloric Intake Stress
Cell signaling: Insulin Resistance 31 Ulanet DB et al. Proc Natl Acad Sci U S A Jun 15;107(24):
32 IR and Cancer risk 32 Increased Cancer Mortality FBS >100 mg/dl NEJM. 2011;364: Esposito K, et al. Dia Care. 2012;35:
Glycemic Load and Colon cancer Prospective, observational study of 1011 stage III colon cancer patients reporting dietary intake during and 6 months after participation matched to 253 controls in an adjuvant chemotherapy trial. The median follow-up from the time of completion of Q1 was 7.3 years. Higher dietary glycemic load was associated with statistically significant worse disease-free, recurrence-free, and overall survival. Stage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted hazard ratio (HR) for disease recurrence of 1.79 (95% confidence interval [CI] = 1.29 to 2.48), compared with those in the lowest quintile (HR = 1) (Ptrend across quintiles <.001). Increased glycemic load was associated with decreased overall survival (Ptrend across quintiles <.001). These associations were strongest for overweight patients (BMI > 25; HR 2.26) 35 Meyerhardt J, et al. J Natl Cancer Inst Nov 21;104(22):
Nutritional influences on IGF-1: Walnuts An elevated fat (20% of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20% of energy as soy bean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8 % of energy as soy bean oil) diet in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model. No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumor weight and growth rate were reduced in the walnut diet group. Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks. The walnut diet's beneficial effects probably represent the effects of whole walnuts’ multiple constituents and not via a specific fatty acid or tocopherols. 36 Davis PA, et al. Br J Nutr Nov 28;108(10):
37 Cinnamon and IR Cinnamon promotes insulin signaling via selective phosphorylation of the IR, thereby reinstating insulin sensitivity –This causes increased cellular uptake of glucose Activates peroxisome proliferator-activated receptors (PPARs). –PPARs regulate insulin resistance and PPAR agonists are used in the treatment of DB2 and IR. Cinnamon reduces inflammation by decreasing IL-1B, IL-6, and TNFa mRNA. 37 Huang B. et al. J Agric Food Chem Apr 27;59(8):
38 Clinical studies with cinnamon Rafehi H. et al. Diab Obesity Metab. 2012;14:493-99
39 Blueberries and IR 39 Six week DBRCT of 32 obese, nondiabetic, insulin-resistant subjects. –Randomized to consume a smoothie with 22.5g blueberry bioactives from freeze dried whole blueberry powder or equivalent smoothie without the blueberry twice daily Provided equivalent of 2 cups fresh whole blueberries –Insulin sensitivity improved more in blueberry group than in placebo group (p=0.04) Stull A. et al. J Nutr. 2010;140(10):1764-8
Berberine Berberine restores insulin sensitivity via: Activation of AMPk Reduction of hepatic gluconeogenesis (epigenetic effect) Inhibition of fatty acid synthesis in liver (and decrease of fatty liver) RCT of 36 adults with DB2 x 3mo Randomized to 500mg Berberine TID or 500mg Metformin TID There were equivalent blood glucose lowering effects (P<0.01) Continued use of Berberine resulted in improvement of HOMA-IR reduced by 44.7% (P<0.001), lowered FBG, HgA1c, LDL-C. 40 Xia X. et al. Plos One. 2011;6(2):e16556 Yin J. et al. Metabolism. 2008;57:712-17
41 Tocotrienols Tocotrienols, vitamin E isomers, with increased flexibility and smaller (less methylated) heads, allowing for increased antioxidant and anti-inflammatory activity over tocopherols. Tocotrienols reduce triglyceride accumulation (thereby reducing increased adiposity) –Tocotrienols improve glucose and insulin tolerance and reduce inflammatory cell infiltration in a rodent model of human metabolic syndrome. –Tocotrienols activate PPAR which increases insulin sensitivity by restoring Akt pathway function. –Tocotrienols also exert direct antiinflammatory effects: Reduce NFkB, TNFa, COX-2 Wong WY et al. Nutrients. 2012;4(10): Fang F et al. Mol Nutr Res. 2010;54(3): Yam ML et al. Lipids. 2009;44(9):787-97
Cancer Determinant: Immunity The body’s first and last line of defense Cancer, arising from self, is likely to create immune tolerance. Cancer cells secrete IL-10 which activates T regulatory (suppressor) cells and downregulates dendritic type 1 cells 42 Huang RP, et al. Cancer Res 1995;55(21):
A tumor’s immunological fate 43
Th1: counterweight against tumor- derived immune escape Stimulation of IL-12 producing DC (APC) with subsequent activation of tumor specific cytotoxic T cells (CD8) is the goal of immunologic tumor destruction. 44
The pivotal role of the type 1 Dendritic cell 45 Immuno- suppression associated with cancer leads away from Dendritic cell type 1 towards Dendritic cell type 2 development This shift promotes regulatory T cell activation and recruitment into tumor sites, suppresses T helper 1 (TH1)- dependent, cytotoxic T lymphocyte responses. Rissoan MC, et al. Science, 1999;283(5405): Whiteside TL, Semin Cancer Biol, 2006;16(1):3-15.
Immune-mediated tumor destruction 46 Tumor cell Lysed Tumor cell CD8 cytotoxic T-cell CD4 helper T-cell Ag-presenting Immune cell Uptake of tumor cell protein fragments MHC II Activation of CD4 T-cell TH1 cytokines: IL-2, IFN-γ, TNF-β MHC I Lysis NK cell B cell Ab-dept. Cellular cytotoxcity TH2 cytokines: IL4-6, IL10 Lysed Tumor cell NK cell
Melatonin o Over 1534 scientific publications on melatonin and cancer o Over 88 human clinical trials on melatonin in cancer o 41 Randomized Clinical Trials o In a meta analysis of 8 RCT’s in solid tumor cancers (n=761), 20mg of melatonin po nightly in conjunction with chemo or radiation. o Melatonin significantly improved the complete and partial remission (16.5% vs. 32.6%; RR = 1.95, 95% CI, ; P < ) o Melatonin improved 1-year survival rate over control (52.2% vs. 28.4%; RR = 1.90; 95% CI, ; P = 0.001) o Melatonin significantly decreased radiochemotherapy-related side effects including: o thrombocytopenia (19.7 vs. 2.2%; RR = 0.13; 95% CI, ; P < ) o neurotoxicity (15.2 vs. 2.5%; RR = 0.19; 95% CI, ; P < ) o fatigue (49.1 vs. 17.2%; RR = 0.37; 95% CI, ; P < ). o Effects were consistent across different types of cancer. No severe adverse events were reported. 47 Wang et al. Cancer Chemother Pharmacol May;69(5):
Medicinal mushrooms Systematic review and meta-analysis of 13 trials that met inclusion criteria Cumulatively, there was 1,284 patients in the PSK/PSP group (49.6%) and 1,303 in comparison groups(50.4%) Overall survival at 5 years was improved in the PSK/PSP group P< ; RR=1.14 Over all cancers, there was a 9% absolute reduction in 5- year mortality (one additional patient alive for every 11 pts treated) Effects were more evident for breast, gastric or colorectal cancer versus esophageal or nasopharyngeal 48 LY Eliza W, et al. Recent Patents Inflamm & Allergy Drug Discovery. 2012;6(1):78-87.
Antioxidant status: Polarizing the immune response Glutathione (GSH) is the most important intracellular antioxidant. Depletion of GSH results in lowered Th1 and increased Th2 activity. Conversely, repletion of GSH increases Th1 and decreases Th2 activity. Thus, the antioxidant status of the cell influences the Th1 polarization of the immune response. 49 Peterson JD, Herzenberg LA, Vasquez K et al. Proc Nat Acad Sci USA,1998 Murata Y, et al., Int Immunol, 2002.
Forest Bathing 50
Forest Bathing: NK cells Forest bathing increases NK activity, number of NK cells, and intracellular anti-cancer proteins in lymphocytes. A forest bathing trip consists of time breathing in volatile substances, called phytoncides (wood essential oils), which are antimicrobial volatile organic compounds derived from trees, such as a-pinene and limonene. 12 healthy male subjects, ages years, experienced a three-day/two-night trip to either a forest or a city, in which activity levels during both trips were matched. Blood and urine were sampled on the second and third days during the trips, and on days 7 and 30 after the trip. Similar measurements were made before the trips on a normal working day as the control. Phytoncide concentrations in forest and city air were measured. 51 Li Q, Morimoto K, Kobayashi M et al. Department of Hygiene and Public Health, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
Forest Bathing Results The forest bathing trip significantly increased NK activity and the numbers of NK, perforin, granulysin, and granzyme A/B-expressing cells and significantly decreased the concentration of adrenaline in urine. The increased NK activity lasted for more than 7 days after the trip. In contrast, a city tourist visit did not increase NK activity, numbers of NK cells, nor the expression of selected intracellular anti-cancer proteins, and did not decrease the concentration of adrenaline in urine. Phytoncides, such as alpha-pinene and beta-pinene were detected in forest air, but not in city air. This pilot study illustrates the profound healing effect of Nature. 52
Holistic Cancer Perspective The genetic, epigenetic and tissue changes that culminate in cancer are reversible. There is tremendous potential for the therapies of lifestyle & natural medicine to reverse errant epigenetic alterations, to restore a healthy tissue matrix and to control carcinogenesis. 53
And, of course the best treatment is lifelong 54
Resources 55 Definitive Guide to Cancer: An Integrative Approach to Prevention, Treatment and Healing (3 rd ed.) Five To Thrive: Your Cutting-Edge Cancer Prevention Plan By Lise Alschuler, ND, and Karolyn A. Gazella Five To Thrive Live! Talk radio M – F 5p PT / 8p ET on Naturopathic Specialists, LLC.