THE BIOLOGY and ENVIRONMENTAL EPIGENETICS OF CANCER - PowerPoint Presentation

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THE BIOLOGY and ENVIRONMENTAL EPIGENETICS OF CANCER

Mitchell Gaynor, MDFounder and President, Gaynor Integrative OncologyAssistant Clinical Professor of Medicine,Weill-Cornell Medical CollegeScientific AdvisorEnvironmental Health TrustSlide2

Cancer and Environment

One in 3 Americans will hear the words “You have cancer”More Americans are surviving cancer – 9.8 million Americans in 2001 vs 3 million living with cancer in the early 1970s

Cancer rates are increasing in many categories:

- In 2003 cancer cases in US

increased 3.8%

- Non-Hodgkin Lymphoma rates

tripled since 1950’s

- 1 in 7 women

now develop

breast

cancer, compared to

1 in

22 in 1940Slide3

Cancer Incidence

Americans had a 132% increase in melanoma, the deadliest skin cancer between 1979 - 1998In New York State – Rates of non-Hodgkin's lymphoma increased 76% for males and 49% for females between 1975 - 1994

In the US, incidence of lymphoma has tripled since 1950

Cancer is the leading cause of disease-related deaths in children under the age of 15 and about one-third of childhood cancers are leukemiaSlide4

NEJM Twin Study

Identical twins developed same disease only 10% of the time

Both develop either breast, colon or prostate cancer 14 – 30% of the time

New England Journal of Medicine, 2000Slide5

Are we born with our genetic destiny or can it be changed?

Agouti mice-- epigenetic changes

carried

across generations

(Waterland and Jirtle, Mol.Cell.Biol.23:5293-5300, 2003) (Env.Health Perspect 2006 April,114(4) 567-572)

Nutritional genomics vs. toxicogenomics

Epigenetics :DNA methylation and histone modificationSlide6

ENDOCRINE DISRUPTORS

Vinclozalin, methoxychlor

Plastics(phthalates),pesticides

Reik,W et.al.2001Epigenetic reprogramming in mammalian development. Science 293:1089-1093

Dolinoy et.al. Proc Natl. Acad Sci 104:13056-13061,2007Slide7

Inherited Breast / Ovarian Cancer

BRCA1 or 2 MutationFuture of Predictive GenomicsWomen have an 82% lifetime risk of breast or ovarian cancerRisk has increased since 1940

Risk of breast cancer 24% if born before 1940 but 67% if born after 1940

Risk of ovarian cancer was twice as high for BRCA1 carriers and 23% higher for BRCA2 carriers if born after 1940

King et.al Science 24 October 2003 Vol.302 P 643-646Slide8
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Only 10% of All High-Volume Chemicals

Have Been Thoroughly Tested by the EPA More than 80,000 chemical compounds have been developed in the past 50 years. There are 3,000 high-volume chemicals in use in the U.S. These are most likely to be dispersed in air, water, food crops, communities and homes. Only 10 percent have been thoroughly tested.Only 43 percent have been tested minimally.Only 7 percent have been studied for possible effects on development.

Landrigan, Philip J., M.D., “Environmental Pollutants and Disease in Children, Estimates of Morbidity, Mortality and Costs for Lead Poisoning, Cancer and Developmental Disabilities,”

Environmental Health Perspectives,

Vol. 110, No. 7, July, 2002.Slide10

Wild Species Loss

25% of the world’s species of mammals and 12% of the world’s species of birds are now in danger of extinction International Union for Conservation of Water and Natural ResourcesSlide11

Natural Compounds in Cancer Prevention and Treatment

Compounds which inhibit cancer cell proliferation directly (bee propolis, turmeric, EGCG, genistein, resveratrol, selenium, vitamin E)

Compounds that act by indirect means to inhibit cancer progression (vitamin C, anthocyanidins, proanthocyanidins)

Compounds which stimulate the immune system (maitake/shitake mushrooms, ginseng, glutamine, melatonin)Slide12

Gaynor Integrative Oncology

Cancer treatment which incorporates epigenetic science, nutritional factors, patient history of exposure to environmental toxicants, and the impact of life stressors. This field includes the interaction of proactive techniques such as music therapy, chi gong, acupuncture, yoga, and nutrition to influence effectiveness or decrease toxicity of cancer therapies. Slide13

Classes of Pollution

Persistent organic pollutants – PCB’s, dioxin, furans, pesticide residue

PM 10 and PM 2.5 – Tiny particulate matter in air. Emitted from diesel combustion, coal-burning kilns and hazardous waste burning smokestack

Asbestos

Nuclear waste

Metals: Lead, Arsenic, Mercury

Microwaves, electromagnetic fields (EMF’s) and UV radiationSlide14

CUTTING EDGE RESEARCH

NUTRITIONAL GENOMICSTOXICOGENOMICSSlide15

Toxic Compounds: Present in Over 75%

of All Samples Tested by the EPASince 1976, the Environmental Protection Agency (EPA) has been measuring toxins from fatty tissue of both autopsies and patients undergoing elective surgery in the U.S. 20 toxic compounds, including OCDD (a dioxin), styrene,1,4-dichlorobenzene, xylene, toluene, DDE and PCBs were found in more than 75 percent of all samples.Slide16
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PBDEs

Polybrominated diphenyl ethersMandated Flame retardantUsed in upholstered furniture, foam mattress and cushions

Associated with disruption of thyroid function, slowed brain development, cancerSlide19

PBDEs

(polybrominated diphenyl ethers)Ethers that are used as flame retardantsLevels in harbor seals increased 100 fold between 1989 and 1998

Levels in human tissue in US were 10-40 times as high as levels reported in earlier Swedish study

Levels of PBDEs are now doubling every 5 years

San Francisco Bay Area – Breast tissue samples of women showed highest levels in the world, up to 25 x greater than European samples

Petreas, Myrto et.al. Env. Health Perspective, Vol 3, No. 9, July 2003Slide20

Solvents

Chlorox (chlorine bleach), Freon (CFC) are examples of the 30,000 branded solvents available to households and industryUses: thinning paint, glues, washing electronics, dry cleaning fabrics

Most used trichloroethylene and methylene chloride

1.5 billion pounds produced yearly in US

Only 1% are reused or recycled

94% released into environment – mostly air

Many tied to cancer, birth defects, liver and kidney damageSlide21

Parabens

Preservatives used in antiperspirants and soap products

Found in high concentration in human breast cancer

Can also mimic the hormone estrogen

Women who applied deodorant or antiperspirant twice a week were found to be almost 15 years younger when diagnosed with breast cancer

McGrath et.al European Journal of Cancer Prevention Vol.12, Dec. 2003Slide22

Phthalates

Endocrine disrupting chemicals used in plastics to make them softerFound in nail polish, soft plastic toys for infants, solvents, flavorings, perfumes, skin moisturizers

PHP - common phthalate in hair sprays, cosmetics, shampoo

PHP linked to birth defects and reproductive impairment in animalsSlide23

ATSDR PUBLIC HEALTH ASSESSMENT- HUNINGTON LANDFILL, SUFFOLK COUNTY

“In April 1994 the NYS DOH completed a study of the occurrence of breast cancer on Long Island. The study found an association between living near chemical facilities on Long Island and the risk of breast cancer in post- menopausal women.”“ Groundwater downgradient from the landfill is contaminated with chlorinated solvents and metals. From 1973 to 1994 the SCDHS sampled 180 private drinking water wells. Elevated levels of some VOC’s… were detected in 50 wells… NYS DOH requested all homes with private wells contaminated or threatened by groundwater contaminant plume from the landfill be connected to public water.”Slide24

Tupperware, rubbermaid bowls are made from polyethylene are safer options

Tips for the Home

Avoid microwaving with wraps which contain dangerous plasticizers

Avoid upholstered furniture or foam products that have been treated with

PBDEs

. None of Ikea’s upholstered furniture contains PBDEs.Slide25

Tips for the Home

Heating plastic wrap with olive oil in a microwave results in concentration of xenoestrogens 500,000 times greater than the minimum amount of estrogen needed to induce cancer cells in a test tube.

Bottom line – Never microwave in plastic or cover in plastic wrap. Use glass or ceramic containers instead

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Tips for the Home

Avoid dishwasher detergents with chlorine and phosphates that release volatile organic compounds as vaporized mist

Practice Safe Phone and Safe Tech

Distance is your friend

Avoid using phones with weak signals

Do not keep phones next to the body

Use wired rather than wireless when possible Use speakerphone or wired headsets

Sleep in the dark & quietSlide27

Tips for the Home

Baking soda will clean sinks, tubs and toilets

Vinegar in a pump-spray bottle cleans mirrors, windows and chromeSlide28

Tips for the Home

Vegetable oil with lemon juice is good furniture polishUse non-chlorine bleach

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Tips for the Home

Chlorine bleach is potentially carcinogenic and toxic to lungs. Its byproducts that contaminate air : chloroform, trihalomethanes and chlorinated hydrocarbons

Other chemicals in chlorinated products act as xenoesrogens, thus increasing risk of breast cancerSlide30

Tips for the Home

Hydrogen peroxide – a better choice than bleach – breaks down to hydrogen and waterBleaches made from hydrogen peroxide now availableSlide31

Tips for the Home

Borax is safer laundry detergentUse non-bleached coffee filters

Skip

synthetic air

fresheners – use all natural scented oils and candlesSlide32

Tip for the Home

Look for American National Standards Institute (ANSI) Label for low-emitting formaldehyde household products

Look for carpeting made

from jute, cotton or wool

Avoid PVC blinds

Wash permanent press products before using

Info on products with no formaldehyde or other VOC emissions:

www.greenguard.orgSlide33

Tips for the Home

Minimize dry cleaning which uses chlorinated chemicalsHardwood plywood paneling and particle board used in shelving omit VOC’s either in wood itself or from resins and glues used to hold them together

Look for solid wood products certified by the Forest Stewardship Council

Contact Organic Trade Association for more info at www.ota.comSlide34

DETOXIFYING ENZYMES and BREAST CANCER

JOHNS HOPKINS UNIVERSITY STUDYCompared genetic detoxifying enzyme ability of 110 patients with breast cancer vs. 113 controlsAbnormal glutathione-S-transferase genes causing decreased enzyme activity resulted in a fourfold increased risk of breast cancer(Helzlsouer, K. et al., J. Nat. Can. Inst. 1998)Slide35
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Omega-3-fatty acids

Breast cancer patients with higher fat tissue levels of DHA had improved response rates to chemotherapy that those with low levels.

(

Bougnoux

, P, et al. Cytotoxic drugs efficacy correlates with adipose tissue DHA level in locally advanced breast cancer.

Br J Cancer 1999 Apr; 79(11-12): 1765-9

Omega-3-fatty acids have been found to:

Increase chemo drug accumulation within cancer cells

Reduce cancer cells proliferation by inhibiting protein kinase C activitySlide40

Omega 3 Fatty Acids and Cancer Therapy

The efficacy of chemotherapy drugs such as adriamycin, irinotecan, 5-fluorouracil, as well as radiation therapy is enhanced when the diet included (n-3) fatty acids.

“in combination with standard treatments, supplementing the diet with (n-3) fatty acids may be a nontoxic means to improve cancer treatment outcomes and may slow or prevent recurrence of cancer.”Slide41

Omega 3 fatty acids enhance tamoxifen response

Friedrichs,W,et.al. San Antonio Breast Cancer Symposium,2005,(Poster)Mice implanted with breast cancer cells :1 group diet high in corn oil(n-6); group 2 diet high in fish oil(n-3).Further subdivided into Rx with placebo or tamoxifenDiet rich in n-3 restored rsponse in tumors with high Akt activity(associated with aggressiveness and tamoxifen resistance).Slide42

OBESITY VS. DETOXIFICATION

Fat production or fatty acid synthesis depletes stores of NADPH, which is the body’s ultimate reducing (antioxidant) agent. NADPH stores are required for the regeneration of antioxidants (ARE) and glutathione.Slide43

Hyperglycemia and

Cancer Mortality Elevated fasting serum glucose levels were associated with a 27% increase in cancer mortality among men and a 31% increase among women.

JAMA January 12, 2005 - Vol 293, No 2Slide44

Cancer, Diet , Causes

Inflammation/MediatorsOxidative OverloadGlycemic OverloadDetoxificationSlide45

Nutritional Lab Assessment

- B12, folate, mercury, copper, lead levels

- Thyroid function

- Cardio C reactive protein, ESR - Serum 25-OH Vitamin D

. CoQ 10 levels

- Fasting glucose, insulin, Hemoglobin A

1

C

- Cellac Panel

- Natural Killer cells

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EPIC : DIET AND CANCER

May,2004The European Prospective Investigation into Cancer and Nutrition (EPIC) :The study registered 519, 978 participants between 1992 and 2000 in 10 European countries. Cancer incidence and cause-specific mortality to be f/u for several decades.“Diet is the second leading cause (25%) of all cancers”Slide47

Women’s Intervention Study (WINS)

Chlebowski,RT,et al SABCS 2006 Gen. Session5:Abst 32 and JNCI Dec.20062400 women with early breast cancer at UCLA: randomized prospective trial--low fat (less than 20% cal. from fat) vs. controlAt 5.8 yrs; 22% fewer deaths- low fat dietThose with ER-/PR- there was a 66% reduction in mortalitySlide48

Fasting Insulin and Outcome in Early-Stage Breast

Cancer: Results of a Prospective Cohort Study Purpose: Insulin, a member of a family of growth factors that includes insulin-like growth factor (IGF)-I and IGF-II, exerts mitogenic effects on normal and malignant breast epithelial cells, acting via insulin and IGF-I receptors. Because of this and because of its recognized association with obesity, an adverse prognostic factor in breast cancer, we examined the prognostic associations of insulin in early-stage breast cancer.

J Clin Oncol 20(1):42-51, January 1, 2002Slide49

Fasting Insulin and Outcome in Early-Stage Breast Cancer: Results of a Prospective Cohort Study

High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored.J Clin Oncol 20(1);42-51, January 1, 2002Slide50

April 24, 2003

Obesity and Mortality from Cancer in a Prospectively Studies Cohort of U.S. Adults

“death rates from all cancers combined were 52 percent higher (for men) and 62 percent higher (for women) than the rates in men and women of normal weight.”

“We estimate that current patterns of overweight and obesity in the United States could account for 14 percent of all deaths from cancer in men and 20 percent of those in women.”Slide51

ALPHA-LIPOIC ACID

Antioxidant that helps reduce free radicalsImproves insulin sensitivity, reduces insulin resistanceAppears to improve glucose transport Dosage: 200-800mg dailySlide52

NF Kappa B and AP 1

Transcription factors produced in excess by cancer cells

Stimulate cancer cell proliferation

Inhibit apoptosis

Enhance inflammation

Increased NF Kappa B activity in cancer cells is associated with poorer prognosis, invasiveness and metastasis

(Nakshatri H, et al. Mol Cell Biol 1997 Jul; 17(7): 3629-39

Bours V, et al. Biochem Pharmacol 1994 Jan 13; 47(1): 145-9)Slide53

ANGIOPREVENTIVE COMPOUNDSSlide54

ANGIOPREVENTIVE COMPOUNDS

Araldi EM

et al. Curr Cancer Drug Targets. 2008, 8(2):146-55Slide55
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Curcumin-Induced Antiproliferative and Proapoptotic Effects in Melanoma Cells Are Associated with Suppression of Nuclear Factor

KB NF-kappaB plays a key role in cell survival and proliferation in human melanoma Evaluated NF-kappaB inhibition for melanoma treatment.

Curcumin, an agent with known, potent, NF-kappaB- inhibitory activity and little toxicity in humans demonstrated antiproliferative and apoptosis enhancing effects in melanoma cells.

Cancer 2005 Aug 15;104(4)879-90Slide57
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Whole-grains and Cancer

Fermented in the colon---1)Yields short-chain fatty acids(SCFA) 2) SCFAs associated with reduced CRP 3) provides immune protection by supporting GALT.

Improve insulin and glucose responses.

Bioflavonoids, phytates, lignans, stanols and sterols, B- vitamins and minerals.

Ajani et al., J Nutr. 2004 May;134(5):1181-5Slide60

VITAMIN D AND BREAST CANCER

Garland,Cedric et al.(UCSD) AACR 2006Meta-analysis 1,760 women- 25-OH Vit. D levelsMultiple regression analysis: D3 level>52ng/ml assoc with 50% lower risk breast CA compared with levels<12 ng/ml.Previous study (Prev Med 1990:19:614-22): Demonstrated women living closer to the equator, had significantly lower risk of breast cancer deathSlide61

VITAMIN D DEFICIENCY LINKED TO POORER OUTCOME IN BREAST CANCER

Women who had very low 25-OH vitamin D levels were 94% more likely to develop metastases (69% vs. 83% DFS) and 73% more likely to die (74% vs. 85% OS at 11.6 yrs) than women with normal levels at time of diagnosis.37.5% had deficient levels below 5024% had “sufficient” levels over 72{ASCO 2008 Annual Meeting}Slide62

SOY ISOFLAVONES AND BREAST PROLIFERATION

Palomares,M San Antonio Breast Cancer Symposium(2005) (Poster)23 postmenopausal breast cancer (Stage I, II, DCIS) patients at City of Hope National Medical CenterRandomized:Isoflavone tab 100mg/d vs.placebo for 1 yearBx contralat. breast at 0, 6, and 12 mo:Ki67 index decreased from baseline in Rx group by 3.1% vs.0.9% control (6 mo.) and 4.9% vs.4.1% (12 mo.) “Our findings suggest no negative effects of soy and perhaps even a beneficial effect”Slide63
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LIFESTYLE CHANGE-A NEW PROSTATE CANCER RX

?93 men with biopsy proven prostate CAGleason’s score< 7All elected to forego conventional RXRandomized:Vegan diet, exercise, yoga/meditation vs. control groupAfter 1 year PSA decreased in LS group but increase in control (J.Urol)2005.174(3)Slide69

Green Tea and Prostate Cancer

Bertuzzi,S AACR 2005(abstract)30 men with high grade PIN Randomized Control vs 600 mg/d green tea catechinsBx done at 0 and 12 mo9 cases prostate CA control and 1 in Rx group at 1 yearThe 30% incidence at 1 year is c/w literatureNo adverse effects in Rx groupSlide70

METFORMIN

From diabetes to cancer… via angioprevention?• It received approval by the U.S. Food and DrugAdministration (FDA) for Type 2 diabetes in 1994. Metformin is an insulin-sensitizer that reduces blood sugar levels: it reduces hepatic glucose output and increases peripheral glucose metabolismCardiovascular benefit(UKPDS and PRESTO study)Slide71

From diabetes to cancer… via

angiopreventionEpidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients’ survival in type 2 diabetics.Evans JM et al. BMJ 2005Landman GW et al. Diabetes Care 2010A decreased risk of breast cancer was observed in patients with type 2 diabetes using metformin on a long term basis.Bodmer M et al, Diabetes Care 2010FromSlide72

VEGETERIAN PROTEIN SOURCES

Silken Tofu

3oz ¼ block

5 grams/protein

Block Tofu (

in water)

3oz or 1/5 block

12 grams/protein

Tempeh

4oz (½ container)

12 grams/protein

Soy milk

8 ounces

10 grams/protein

Soy beans

½ cup

24 grams/protein

Legumes, beans, lentils

½ cup

6 grams/protein

Soy cheese

1 ounce

7 grams/protein

Nuts

¼ cup

5 grams/protein

Eggs

1

7 grams/protein

Yogurt

1cup

10-12 grams/protein

Cheese

1 ounce

7-10 grams/proteinSlide73

EXERCISE

Aerobic exercise has been shown to reduce insulin resistance by improving blood supply to the muscle, which allows for more glucose uptake into muscle tissue.Exercise should be frequent and regular to be effective.Exercise should involve all the major muscle groups for at least 20-30 minutes 4-5 days/week.

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We Cannot Wait for Absolutes

The Precautionary Principle*We must act on facts and on the most accurate interpretation of them, using the best scientific information. That does not mean we must sit back until we have 100% evidence about everything. Where the state of the health of the people is at stake, the risks can be so high and the costs of corrective action so great, that prevention is better than cure. We must analyze the possible benefits and costs of action and inaction. Where there are significant risks of damage to the public health, we should be prepared to take action to diminish those risks even when the scientific knowledge is not conclusive, if the balance of likely costs and benefits justifies it.

Source: Richard Horton, Editor-in-chief,

Lancet.

*Modified from a 1990 UK Department of the Environment definition.

Lancet

, Vol. 352. No. 9124, 5 July, 1998.Slide75

For More Information www.

DrGaynor.comGaynorWellness.comDrKathrynCollins.comEnvironmentalHealthTrust.org