Download - Modulating Oncometabolic Syndrome: Integrative Diet & Nutrition to Complement Cancer Care
Jeanne M. Wallace, PhD, CNC
Nutritional Solutionswww.nutritional-solutions.net
Integrative NutritionTo Complement Cancer Care
ModulatingOncometabolicSyndrome
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Wallace, PhD, CNC, Jeanne
Indicated no relevant affiliations or financial interests.
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Learning Objectives•Describe integrative nutrition protocols targeting Oncometabolic Syndrome (a cluster of metabolic factors that influence the growth and progression of cancer)
•Choose standard lab testing to assess nutritional factors that may influence cancer outcomes, tailor a protocol to an individual's unique needs, and evaluate the efficacy of the nutrition intervention in modulating these factors.
• Apply a diet to down regulate "Oncogenic Potential" via:a. Phytonutrient modulation of gene expression
b. Dietary & lifestyle guidelines to address insulin resistance
c. Strategies to modulate inflammatory eicosanoids
d. Dietary strategies for anti-angiogenesis
BestCaseSeries SurvivalComparison
GBM IV
4Intl J Radiat Onc Biol Physiol, 2003:57:S135–6.
0%
25%
50%
75%
100%
1 yr 3 yr 5 yr
➤ N=341 consecutive cases GBM IV (1997-2004) from NCI NCCAM Best Case Series submission
➤ Published survival rates for GBM IV [Shaw et al., 2003]
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Other CancersSurvival Data Selected Cases 1999-2009
Sex Age Dx Survival
F 58 IV > 9 yr, 5 mo
M 36 II 9 yr, 5 mo
M 49 IV > 6 yr, 9 mo
F 61 IV 6 yr, 9 mo
F 46 IV 5 yr
M 76 III > 4 yr, 9 mo
M 46 IV 4 yr, 3 moCol
orec
tal
Age Dx Survival
55 IV > 14 yr, 2 mo
57 IIIc > 11 yr, 8 mo
54 IIIc > 10 yr, 5 mo
55 IIIc > 9 yr, 11 mo
57 IIc+BrCa > 9 yr, 2 mo
38 IIIc > 7 yr, 10 mo
67 IIIc > 6 yr, 4 mo
47 IIIc 6 yr, 1 mo
53 IIIc 6 yr
70 IV 5 yr, 9 mo
Ova
rian
Sex Age Dx Survival
M 70 III 4 yr, 1 mo
F 50 IV > 3 yr, 10 mo
M 66 IV > 3 yr, 3 mo
F 59 I > 3 yr, 2 mo
F 64 IV > 2 yr, 11 mo
M 54 IV 2 yr, 9 mo
M 58 III 2 yr, 3 mo
Pan
crea
tic
COX-2CRP
LOX-5
estrogen
leptin
adiponectinVEGF
IGF-1
↑NFkß5-HETE
cortisol
VEGF
bFGF
IL-6
TNF-α
↓ SHBG
↑ Copper
IL-10
fibrin
↓ Antioxidants
insulin
PDGF
↑ Iron
↓ Vit D↓ Zinc
They are influenced by factors in their environment.Cancer cells do not exist in isolation...
7
Oncometabolic Milieu
COX-2CRP
LOX-5
estrogen
leptin
adiponectinVEGF
IGF-1
↑NFkß5-HETE
cortisol
VEGF
bFGF
IL-6
TNF-α
↓ SHBG
↑ Copper
IL-10
fibrin
↓ Antioxidants
insulin
PDGF
↑ Iron
Hyper-coagulability
SystemicInflammation
InsulinResistance
HormoneImbalance
NutrientImbalances
ImmuneIncompetence
Angiogenesis
↓ Vit D↓ Zinc
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“Give me the coding sequences of a chimpanzee and the regulatory mechanisms of a mouse,
and I’ll give you a mouse.”—Susumu Ohno
Evolutionary Geneticist
Understanding Epigenetics
Microbiome
Ecosystem ➠ Gene Expression
PositiveEmotions
Stress
Toxins
Oxidation
Radiation
Infection
Diet
Disease Health
Carcinogens CircadianRhythm
HealthyLifestyle
12
13
NFkßCancer’s MasterSwitch
Curr Allergy Asthma Rep, 2013;13: 44–9. • Curr Signal Transduc Ther, 2006:1:25-52. • Cancer Res, Feb 15, 2007;13(4):1076-82.
TRIGGERS carcinogensoxidationviral infectioninflammationradiationchemotherapy
NF
kß
NFkß Activates 400+ Genes
14Exp Biol Med (Maywood), 2008;233(1):21-31. • Curr Signal Transduc Ther, 2006:1:25-52.
AngiogenesisVEGF, TNF, IL-8
InflammationIL-6, COX-2,
TNF, chemokines
Survival/Anti-apoptosisbcl/bax, survivin
Proliferationmyc, IL-6,
Metastasis5-LOX, CAMs
NF
kß
Spices Inhibit NFkß
Ann NY Acad Sci, Dec 2004;1030:434-41.
anise
basil
black pepper
caraway
cardamom
chili pepper
cinnamon
clove
coriander
cumin
fennel
fenugreek
flaxseed
garlic
ginger
Holy basil
lemongrass
licorice
mint
mustard seed
nutmeg
oregano
parsley
rosemary
saffron
tamarind
turmeric
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Modifying
Gene Expression
Histone modifiers UNWRAP the DNA strand
Methyl groups prevent the DNA strand from being
UNZIPPED
17Epigenomics, 2011;3(4):503-18. • Ann Rev Nutr, 2008;28:347-66.
Histone ModifiersHistone Acetyl-
Transferase
HAT
Histone D-Acetylase
HDAC
Genisteinsoy
Curcuminturmeric, curry
EGCGgreen tea
Seleniumbrazil nuts
Sulforaphanecruciferous veggies
Resveratrolgrapes, wine
Allyl mercaptangarlic
Wrapped
Unwrapped
HDACs
HATs
➠
➡➡➡
➡➡➡
➡➡➡
Epigenomics, 2011;3(4):503-18. • Ann Rev Nutr, 2008;28:347-66.
Methylation Modifiers
Methylation Support
DNMTInhibitors
FolateVitamin B12Vitamin B6
BetaineCholine
MagnesiumZinc
SeleniumSulforaphane
EGCGResveratrolGenistein
18
mRNA
miRNA
microRNA
blocks
protein
assembly
Green tea EGCGCurcuminSoy foodsCruciferous veggies
Genes Nutr, 2011;6(2):93–108. • Pharm Res, 2010 Jun;27(6):1027-41. 20
NFkßswitch off
ModifyHistones
wrap/unwrapMethylation
zip/unzipmicroRNA
veto
spicesturmeric
basilmint
rosemarygarlic
parsleythymesage
saffron
green teacurcumin
cruciferous vegsoy foods berries
red/purple grapescitrusgarlic
brazil nutsbutyrate
leafy greens beets
green teacruciferous veg.
brazil nuts
green teacurcumin
cruciferous vegsoy foods
Biochem Pharmacol, 2010;80(12):1771–92. • Genes Nutr, 2011;6(2):93–108. 21
✤ Prostate cancer patients not electing surgery, radiation, hormone therapy
✤ Gene expression compared after 3 months on diet
✤ Expression of 500+ genes changed
✤Oncogenes were down-regulated
PNAS, 2008 Jun 17;105(24):8369-74.
Diet Alters Gene Expression B
EFO
RE
AFT
ER
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NFkß & Diet Patternin Colorectal Cancer Patients
Clin Nutr, 2010 Feb;29(1):42-6.
High NFkßHigh histological aggressiveness
Low NFkßLow histological aggressiveness
↑ refined carbs↑ omega 6:3 ratio
(≅26:1)↑ alcohol
↑ omega 6:3 ratio (≅6:1)
↑ fiber↑ selenium↑ vitamin E↑ flavonoids↑ β-carotene↑ isoflavones
23
Hyperglycemia & Brain Tumor Survival
4
8
11
15
65-93 94-137 ≥ 138
25
50
75
100
5-Yr OS DFS PFS
NormoglycemicHyperglycemic
Neurol Res, 2010 May;32(4):442-8. J Clin Oncol, 2009 Mar 1;27(7):1082-6.25
Breast3-fold ↑ riskrecurrence over 5 yrs
Int J Cancer, 2006 Jul
1;119(1):236-8.
Ovarian 60% shorter median survival
Gynecol Oncol, 2011 Apr;
121(1):106-11.
Lung(NSCLC)
69% ↑ risk mortality if fasting
glucose ≥ 126
Lung Cancer, 2012 May;
76(2):242-7.
Prostate↑ 2-fold increase risk recurrence (meta-analysis)
J Exp Clin Cancer Res, 2013 Feb 13;32(1):9.
MetSx & Cancer Outcomes
26
Post-OpComplications
40% vs 11% with 11 vs 8 days
hospitalized
Dis Colon Rectum, 2010
Feb;53(2):186-91.
ImmuneSuppression
↑ risk infection during chemo
Diabetes Care, 2008 Oct;
31(10):1972-7.
Increased Estrogen
↑ aromatase activity, ↓ SHBG
production
Obes Rev, 2007 Sep;8(5):395-408.
MetSx correlates with...
27
INDICATOR TARGET*Waist-Hip Ratio women < 0.8, men <1.0
Waist Circumference
women ≤ 35, men ≤ 40”
A1c < 5.0-5.2%
Triglycerides < 110 mg/dL
HDL cholesterol > 50-55 mg/dL
Blood pressure < 120/80
Glucose fasting < 60-90 mg/dL post-prandial < 120 mg/dL
Uric Acid < 5.5 mg/dL
*Based on optimal, Functional Medicine ranges and/or cut-off points associated with improved prognosis in cancer patients (not standard diagnostic criteria).
AssessingBiomarkers of
InsulinResistance
29
Insulin Resistance in Cancer Patients✤ DIET
✤ POOR DIGESTION
✤ STRESS
✤ LACK OF EXERCISE weak-ness, ↓ muscle mass, ↑ adiposity
✤ NUTRIENT DEFICIENCIES vitamin D, chromium, carnitine, CLA magnesium, biotin, vanadium, zinc
✤ TREATMENT EFFECT Beware! These wholesome-appearing foods may be problematic Oncol Nurs Forum, 2012 May;39(3):E275-87.
J Clin Oncol, 2001 May 1;19(9):2381-9. 30
SubstitutionsINSTEAD OF THIS...INSTEAD OF THIS... TRY THIS...TRY THIS...
Food (1 cup)
Glycemic
LOADFood(1 cup)
Glycemic
LOAD
White flour
Whole wheat
76
44
Almond Flour 0White flour
Whole wheat
76
44 Coconut Flour 0
Sandwich bun 18Portobello mushroom 3
Sandwich bun 18Romaine lettuce “wrap” 0
Brown rice 22 Cauliflower “rice” 2
Pasta noodles 22Zucchini “noodles” 1
Pasta noodles 22Miracle Noodles 0
Mashed Potatoes 16 Mashed Cauliflower 4
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CinnamonBerries: blueberries, goji, blk currantChamomile teaAlliums: garlic, onions, leeks, chivesParsleyAvocadoOlive oilFlaxseed meal / Oat bran (soluble fiber)Lemon
Top Foods to Aid Glycemic Control
Diab Metabol Syndr: Clin Res Rev, 2010;4(1):21-40.Diab Care, 2003 Apr;26(4):1277-94. 32
Chronic systemicInflammationhas emerged as a
Hallmarkof Cancer
Proliferation Angiogenesis
Immune Evasion Chemoresistance
Radioresistance
Invasion
Metastasis
InflammationPredictsCancerSurvival
Nutr Cancer, 2001;41(1-2):64-9.
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
% patientssurviving
Time (in days)
Low CRP
High CRP
35
TreatmentEfficacy
50% ↓ CRP predicts response to chemo
in NSCLC
J Med Assoc Thai, 2012 Feb;95
Suppl 2:S199-207.
TreatmentToxicity
more severe low blood counts
Ann Oncol, 2003;14:36-41.
Cachexia↓ appetite
↑ muscle wasting↑ weight loss
Lung Cancer, Jun 2003;40(3):295-9.
QOL ↑ fatigueCancer, 2012
Dec 1;118(23):6005-11.
hsCRP correlates with...
36
Dietary Fats & Inflammation
OMEGA-6 FATS✤ Commercially-raised
meat, poultry, dairy, eggs✤ Most nuts & seeds✤ Vegetable oils—corn, soy,
safflower, grapeseed oil (not olive oil)
ANTI-INFLAMMATORYInhibit tumor growth & progressionAnti-angiogenesis Complement radiation & chemo
PRO-INFLAMMATORYFoster tumor growth & progressionPromote angiogenesisSuppress immune function
PGE₂ LTB₄ PGE₃TXA₂ 5-HETE LTB₅
OMEGA-3 FATS✤Pasture-raised meat,
poultry, dairy, eggs✤Wild cold-water fish✤ Black walnuts, flaxseeds✤Oils of flax, hemp & canola
(unstable/not advisable)
Δ6-Desaturase
↑ Insulin
COX & LOX
PGE₁
37
Comprehensive Anti-Inflammatory Plan
*Annu Rev Pharmacol Toxicol, 2011 Feb 10;51:311-36.
Inhibit NFκßample culinary spices
↓ Lipid Peroxidationhigh ORAC diet
Shift Substratesimprove n-6:3 ratio
COX-2 Inhibitorsapigenin, berberine,
bromelain, curcumin, ginger, quercetin, resveratrol
Optimize Desaturase Function↓ hydrogenated+trans fats, provide cofactors (Zn, Mag,
vitamins C, B3, B6)
5-LOX Inhibitorsallicin, baicalein, berberine, boswellic acid, caffeic acid, curcumin, EGCG, galangin
Improve Insulin Sensitivity
↑ Prostaglandin Clearance
vitamin D*
38
Spices (esp. curry, ginger, garlic, parsley)
Wild, cold-water fish
Pastured-raised meat, dairy, eggs
Hot peppers
Olive oil
Leafy green veggies (spinach, chard, kale)
Cruciferous vegetables
Pumpkin, butternut squash, yam, carrot
Dark chocolate (flavanols)
Berries (blueberries, cherries, raspberries)
Top Foods to QuenchInflammation
39
Copper & Cancer Outcomes
Clin Cancer Res, 2000 Jan;6(1):1-10. • Acta Med Okayama. 1986 Apr;40(2):103-5. • J Surg Oncol. 1991 Mar;46(3):178-81. • JNCI, 1981 Aug;67(2):263-75. • J Gastroenterol, 2003;38(1):45-51. • Ann Thorac Surg, Aug 2008;86(2):383-9. • Clin Cancer Res, 2003
May;9(5):1666-72. • Indian J Pathol Microbiol, 1990 Apr;33(2):171-4. • Ann Oncol, 2013 Feb: PMID: 23406736. • Biol Trace Elem Res, 2001;82(1-3):1-8.
✤ Cancer pts have ↑ serum Cu levels (or Cu:Zn ratio) vs healthy controls
✤ Serum Cu and/or Cp correlates with tumor burden, advanced disease, and survival
✤ Cu levels rise during active disease and fall to normal in remission
✤ Cu depletion ↓circulating endothelial progenitor cells in BrCa pts
✤ Clinical trials of Cu chelation show activity in stabilizing disease
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Contributors to Elevated Copper✤ Dietary supplements
✤ Vegetarian or vegan diet
✤ Adrenal hypofunction
✤ Zinc deficiency
✤ Gluten intolerance
✤ Estrogen dominance
✤ Inflammation (local or systemic)
Significant Food Sources of Copper
Food (100-gm/serving) mg
Liver, veal 15
Paté 15
Liver, beef 10
Oyster 8
Liver, duck 6
Soy flour 5
Shiitake, dried 5
Cocoa powder, unswt 4
Lobster, 6oz 4
www.NutritionData.com
42
Spices (esp. curry, ginger, garlic, parsley)
Berries (all types)
Green tea
Parsley, peppermint, thyme (apigenin)
Curry (turmeric, coriander, cumin)
Garlic
Brazil nuts (selenium)
Cold-water fish / Grass-fed meat (omega-3)
Traditional soy foods
Peanuts/boiled, red grapes (resveratrol)
Top Foods to Suppress Angiogenesis
J Physiol Pharmacol. 2005 Mar;56 Suppl 1:51-67. 43
J Steroid Biochem Mol Biol, 2006 Dec;102(1-5):156-62. • J Steroid Biochem Mol Biol, 2010 Jul;121(1-2):343-8. • Ann Rev Pharmacol Toxicol, 2011 Feb 10;51:311-36. • Nutr Res Rev, 2009 Jun;22(1):82-92. • Biochem J, 2012 Jan 1;441(1):61-76.
Vitamin D and Cancer✤ Induces differentiation (more normal phenotype)
✤ Promotes apoptosis (programmed cell death)
✤ Inhibits invasion, angiogenesis and metastasis
✤ Inhibits estrogen synthesis & signaling (↓ expression of aromatase, down-regulates expression of ER-α)
✤ Plays a role in blood sugar regulation and insulin sensitivity
✤ Anti-inflammatory (prostaglandin dehydrogenase)
45
✤Breast Cancer - deficiency associated with worse prognostic markers (ER- and triple-negative tumors), ↑ recurrence risk (Oncotype scores), ↓ survival
✤Colorectal Cancer - high pre-Dx vitamin D3 associated with ↑ survival
✤Brain Tumor - 27% of pts treated with vit D had tumor regression or remission
✤Prostate Cancer - 30% response rate (≥50% ↓ PSA x median 4 months) in pts treated with vit D (up to 5,000iu/day)
Cancer Epidemiol Biomark Prev. 2011;20(4):717. • J Clin Oncol. 2009 Aug 10;27(23):3757-63. • J Clin Oncol. 2008 Jun;26(18):2984-91. • J Neuro-oncol. 2001 Jan;51(1):57-66. • ASCO Annual Meeting, San Francisco, CA. 2010 Mar 5: #228.
Vitamin D and Cancer
46
ACTIONS D₃ A K₂Differentiation (revert to healthy phenotype) ✔ ✔
Apoptosis (cancer cell suicide) ✔ ✔ ✔
Anti-angiogenesis ✔ ✔
Inhibit invasion / metastasis ✔ ✔ ✔
Improve insulin sensitivity ✔ ✔
Reduce estrogen (block aromatase, ↓ ER) ✔ ✔
47
Fat-Soluble Vitamins & Cancer: Emerging Picture of Synergy
SimilarCases:Divergent Outcomes
Susan
Dx OvCa IIIc
Age 48
Ht/Wt 5’4” • 140 lbs
BMI 24
S/P TAH, T/C x 6
Labs WNL
Hx N/C
Sally
49
TEST TARGETCRP
high sensitivity or cardio-C-reactive protein
≤ 0.8-1.0 mg/L
A1c& insulin resistance panel
≤ 5.0-5.2%
Vitamin D325-OH-cholecalciferol
50-75 μg/dL
Free Copperserum Copper minus (3 x Ceruloplasmin)
≤ 10-15
Fibrinogen 200-325 mg/dL
Assessing OncometabolicParameters
50
hs-CRPInflammation ✘
✘ A1cInsulin Resistance
✘ Vitamin D₃Differentiation ✘
Copper & Ceruloplasmin
Angiogenesis✘
✘ FibrinogenBlood Viscosity
Different Stories Emerge
Susan Sally
51
Individualized Nutrition Support
Screen for interactions/contraindications.
hs-CRP
Copper
Vitamin D₃
A1c
Fibrinogen
Vitamin D₃
Bromelain ✔
Curcumin ✔
Quercetin ✔
✔ Fish oil ✔
✔ Blood Sugar Support
✔ Ginkgo biloba
✔ Vitamin D3 ✔
Molybdenum ✔
Zinc ✔
Susan Sally
52
Hyper-coagulability
ChronicInflammation
InsulinResistance
HormoneImbalance
NutrientImbalances
ImmuneIncompetence
Angiogenesis
53
✤ Individualize nutrition protocols ✤ Prioritize self-care strategies✤ Navigate nutrition controversies
Use model to guide choices
melatoninleptin
IGF-1
cortisol
↑ Copper
insulinInsulinResistance
HormoneImbalance
↓ Vit D↓ Zinc
COX-2
CRP LOX-5↑NFkß
VEGF
Inflammation
BloodViscosity
Angiogenesis
ImmuneCompetence
IL-10
HIF1-αFBG
54
Food is Powerful Medicine“Three times a day,
day after day, we are eating foods
that can influence our genes and help
us fight cancer...”—David Servan-Schreiber, MD
www.Nutritional-Solutions.netJeanne M. Wallace, PhD, CNC
Michelle Gerencser, MS • Patrice Surley, MH, NC
Vegetarian/Vegan DietVegetarian/Vegan Diet Omnivore/Paleo DietOmnivore/Paleo DietPRO’s CON’s PRO’s CON’s
↑ Phytonutrients
↑ Fiber
↓ nitrates, HCAs & PAHs
↓ Toxins?*
↑ Copper / ↓ Zinc
↓ Protein
↑ Insulin
↓ CLA
↓ Omega-3s
↓ Vit A (retinol)
↓ Copper / ↑ Zinc
↑ Protein
↓ Glycemic
↑ Omega-3
↑ CLA
↑ Vit A (retinol)
↑ Tocotrienols, carotenoids, folate
Excess Omega-6s (if ≠grass-fed sources)
↑ Nitrates, HCAs & PAHs (carcinogens in processed, grilled/charred meats)
↑ Toxins? *
Crowd Out Phyto’s (if ↓ fruit/veggie intake)
Iron Excess?
*Mean DDT residues: vegetarian diet 239µg/person (range 124-288); non-vegetarians 225µg (range 138-263). Sci Total Environ. 1988;76:139–46.*Mean DDT residues: vegetarian diet 239µg/person (range 124-288); non-vegetarians 225µg (range 138-263). Sci Total Environ. 1988;76:139–46.*Mean DDT residues: vegetarian diet 239µg/person (range 124-288); non-vegetarians 225µg (range 138-263). Sci Total Environ. 1988;76:139–46.*Mean DDT residues: vegetarian diet 239µg/person (range 124-288); non-vegetarians 225µg (range 138-263). Sci Total Environ. 1988;76:139–46.
✤ Not estrogen, rather SERM - in vivo competes with estrogen and xenoestrogens
✤ Modulates estrogen via many pathways - ↑ SHBG, ↓ circulating estrogen, ↑ 2:16-OH estrogen ratio
✤ Rodents metabolize soy differently - lower isoflavone conjugation leads to 20-150-fold ↑ circulating levels than in humans
FAQ: Is SOY safe forER+ breast cancer?
Population Findings ReferenceMeta-Analysis:
9,514 US & Asian BrCa pts over
~7.5 yrs
↓Risk of recurrence in those eating soy foods
Am J Clin Nutr. 2012 Jul;96(1):123-32.
3,088 U.S. BrCa pts followed 5 yrs
↓ mortality with increasing intake soy
isoflavones
Cancer Epidemiol Biomark & Prev. 2011;20(5):854-8.
5,042 Asian BrCa pts, followed 5 yrs
↓ risk mortality and ↓ recurrence in those
with higher soy intake
JAMA. 2009 Dec 9;302(22):2437-43.
1,954 U.S. BrCa pts, followed 6 yrs
60% ↓ rate of recurrence with high isoflavone intake in
post-menopausal pts on Tamoxifen
Breast Cancer Res Treat. 2009 Nov;118(2):395-405.
50 human clinical trialsn = 8,521 pts (>5,000 given antioxidants during treatment)No evidence of interferenceEnhanced cytotoxic efficacy of chemotherapyIncreased survival time
Review
Alt Ther Health Med, 2007 Mar-Apr;13(2):40-7.
FAQ: Do antioxidants interfere with cancer treatment?✤ Differential uptake - ↑ intake in cancer cells,
results in pro-oxidant effect
✤ ↑ Oxidation leads to ↑ gene instability - excessive oxidation fosters more aggressive tumor behavior
✤ ↑ Oxidation leads to ↓ cell proliferation - but cytotoxic treatment targets rapidly dividing cells
✤ ↑ Oxidation activates NFkß - which confers radioresistance and chemoresistance
✤ Foods vs supplements - foods have much ↑ORAC (antioxidant effect) than supplements!
80% ↓ risk of progression and 87% ↓ risk of mortality in pts with BOTH ↑ antioxidant status and ↑ biomarkers of oxidation
Oxidation vs Antioxidants: It’s
not a war....
BMC Cancer 2009;9:458-69.