Food, Facts and Fantasies: Can Your Diet Really Reduce Cancer Risk?

Nutrition Science Research GroupNutrition Science Research GroupDivision of Cancer PreventionDivision of Cancer Prevention

National Cancer InstituteNational Cancer InstituteBethesda, MD 20892Bethesda, MD 20892

J. A. MilnerJ. A. Milnermilnerj@mail.nih.govmilnerj@mail.nih.gov

Unprecedented Opportunities Exist for Expanded Use of Foods and Components to Achieve Genetic

Potential, to Increase Productivity and Decrease Risk of Disease

While we have come a long way since this 1940’s United Kingdom Advertisement, we still can not identify who

will and will not benefit from dietary intervention strategies

Fruits, Vegetables & Cancer Prevention

Variety or Category % Positive

Vegetables 80% (59/74)

Fruits 64% (36/56)Raw vegetables 87% (40/46)

Cruciferous Vegetables 69% (38/55)Allium vegetables 77% (27/35)

Green vegetables 77% (68/88)Carrots 81% (59/73)

Tomatoes 71% (36/51)

Citrus Fruit 66% (27/41)

WCRF/AICR Expert Committee Conclusions

DNA

Nutritional Genomics and Proteomics

Proteins

Enzymes, structural,Enzymes, structural,Transport,signaling Transport,signaling caused by caused by phosphorylation, phosphorylation, glycosylation, etc.glycosylation, etc.

mRNA

CH3-DNAGenomic Post-translational

BioactiveFood

Components

Epigenomic

< 300 mg Caffeine > 300 mg

6

-12

0

-6

Vitamin D Receptor Genotype

TT Tt tt TT Tt tt

S

pine

Bon

e M

ass

Den

sity

(%

)Influence of Caffeine on Bone Mass May Depend on Genes

Rapuri et al. Am J Clin Nutr 2001 Nov;74(5):694-700

Diet-Gene Interactions in Colon Cancer

Yang et al, Cancer Res. 61, 565, 2001

0 4 8 12 16 20 24 28 32 360

10

20

30

40

50

60

70

80

90

100

Weeks

Per

cen

t su

rviv

alp21+/+ AIN-76A Diet

p21+/- AIN-76A Diet

p21-/- AIN-76A Diet

p21+/+ Western Diet

p21+/- Western Diet

p21-/- Western Diet

Selenium Placebo RR 97% CISkin Cancer

Squamous cell 218 190 1.14 0.93-1.39Basal cell 377 350 1.10 0.95-1.28

Cancer (- Skin)Lung 17 31 0.54 0.30-0.98Prostate 13 35 0.37 0.18-0.71Colorectal 8 19 0.42 0.18-0.95Breast 9 3 2.88 0.72-16.5

All Sites (- Skin) 77 119 0.63 0.47-0.85

Selenium & Skin Cancer Prevention Trial

Clark et al. JAMA 276: 1957, 1996.

Phase III trial with 1,312 skin cancer subjects

Se (200 g) as Brewers Yeast vs. Placebo, follow-up 6.4 yrs

Prostate Cancer Prevention Selenium and Vitamin E

Cancer Prevention Trail (SELECT) ($175M)32,000 men, age >55 (> 50 for Black Men)

Selenium 200 ug/dVitamin E 400 mg/d

Vitamin E Placebo

Selenium

7 + Years TreatmentEndpoint Prostate Cancer Incidence

Early Biomarkers NeededIdeal Qualities:• Readily accessible • Easily & reliably

assayed• Differentially

expressed• Directly associated

with disease progression

• Modulable• Predictive

MOLECULE

MACROMOLECULE

CHROMOSOME

ORGANELLE

CELL

TISSUE

ORGAN

ORGANISM

Diet May Influence Genetic & Epigenetic Events Associated with Several Cancer Processes

DNA Repair

Hormonal Regulation

Carcinogen Metabolism

Apoptosis

BioactiveFood

Components

DifferentiationCell Cycle

U54 RFA Review Nov

Numerous Dietary Components Can Alter Genetic and Epigenetic Events

Essential Nutrients- Ca, Zn, Se, Folate, C, ENon-Essential

Phytochemicals- Carotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl Sulfur

Zoochemicals - Conjugated linoleic acid, n-3 fatty acidsFungochemicals - - Several compounds in mushroomsBacteriochemical - - Those formed from food fermentations and those resulting from intestinal flora

Mariadason et al, Cancer Res . 60, 4561, 2000

.

Gene Expression in Human Cultured Colon Cells

Red - increasedGreen - decreasedBlack - unchanged

Butyrate Curcumin

150 mg

3 grams

150 grams

MARKET STAGE BROCCOLI

3-DAY SPROUTS

FREEZE-DRIEDSPROUT EXTRACT

All preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)

How Should We Consume Bioactive Food Components?

S S

ARE

keap-1 nrf2

keap-1

nrf2

nrf2smallmaf

Isothiocyanates(OLTIPRAZ)

Cytoplasm

Nucleus

OLTIPRAZ

Gene expression

HS SH

“antioxidant responsive element”

GS

T A

CT

IVIT

Y(n

mo

l/m

in/m

g)

Nrf2 GENOTYPE

CONTROL

D3T

0

1000

2000

3000

4000

5000GST

0

40

80

120NQO1

CONTROL

OLTIPRAZ

wild-type nrf2-deficient

a

aa,b

a

a,ba

NQ

O1

AC

TIV

ITY

(nm

ol/m

in/m

g)

Effect of Nrf2 genotype on induction of GST and NQO1 activities by oltipraz in mouse liver (Ramos-Gomez et al. Proc Natl Acad Sci U S A 2001;98:3410)

Oltipraz (drug) and

isothiocyanates (nutrient)

have similar mechanism of action

Tea (Camellia sinensis)

Green Tea Black Tea

30-40% Catechins 3-6% Caffeine~310 mg polyphenols per 6 ounces

3-10% Catechins 2-6% Theaflavins> 20% Thearubigens 3-6%  Caffeine~340 mg polyphenolsper 6 ounces

Dried

Tea Leaves

Crushed tea leaves

Polyphenol oxidase

Oxidation,Polymerization

O

OR 2

HO

OH

OH

R1

HO

Yang CS. Personal Communication

Tea and Cancer Prevention

Camellia Sinensis

Yang CS. Personal Communication

SkinLiver

Colon

Oral

Esophagus

LungStomach

ProstateMammary

Tomato VarietiesTomato Varieties

Types of Bioactive CompoundsCompounds May Vary with New Varieties

Recent Epidemiologic Studies of Lycopene and Cancer Risk

Cancer Type of Study Reference

Breast Cohort Dorgan et al. Can Cau Cont 9: 89-97,

1998

Colon Case-control Franceschi et al. Int J Cancer 72:56-61,

1997

Lung Case-control Agudo et al. Eur J Cancer 33:1256-61,

1997

Prostate Cohort Giovannucci et al. J Natl. Cancer Inst. 87:1767-76,

1995

Recent meta-analysis of Data from 11 trials concluded The random-effects relative risk (RR) estimate for raw and cooked garlic and colorectal cancer was 0.69 and for stomach was 0.53. Fleischauer, et al. Amer JClin Nutr 72, 1047, 2000.

Prospective cohort study with 41,837 women age 55 to 69, examined 127 food items. “The strongest association in the present study was that for garlic consumption, with an approximate 50% lesser risk associated with high consumption.” Steinmetz et al. Amer. J. Epidemiology Steinmetz et al. Amer. J. Epidemiology 139:1, 1994139:1, 1994

Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts

a

b b

0

250

500

750

1000

D

NA

Ad

du

cts

(nm

ol A

dd

uct

s/m

ol D

NA

)

Control Peel/Crushed

30 seconds

60 seconds

Microwave/ Peel/Crushed

a

Song and Milner J Nutr 1999;129:657-61

Indole 3-carbinol changes site of hydroxylation of estradiol (>2 and <16 OH). Causes depression in tumor growth and apoptosis.(Telang, et al. PSEBM 216: 246: 1997).(Telang, et al. PSEBM 216: 246: 1997).

How Much of A Given Food is Needed

Name T/C (Ave) p valueALOX5AP--arachidonate 5-lipoxygenase-a 0.451 0.016BMP7--bone morphogenetic protein 7 0.309 0.017ERCC6--excision repair cross-complemen 0.455 .046ESR1--estrogen receptor 1 0.415 0.001EXTL3--exostoses (multiple)-like 3 0.509 0.011GATA3--GATA-binding protein 3 0.521 0.013HMG2--high-mobility group (nonhistone 0.479 0.011Homo sapiens cDNA FLJ14201 fis, clone 0.444 0.015Homo sapiens clone 23836 mRNA sequence 0.526 0.026KIAA0165--extra spindle poles, S. cere 0.532 0.003KRT7--keratin 7 0.505 0.001LAP18--leukemia-associated phosphoprot 0.528 0.013NRCAM--neuronal cell adhesion molecule 0.482 0.016SFRP5--secreted frizzled-related prote 0.498 0.048TCF3--transcription factor 3 0.528 0.034UGDH--UDP-glucose dehydrogenase 0.536 0.029Unknown 0.488 0.008Unknown 0.481 0.015Unknown 0.479 0.019ZXDA--zinc finger, X-linked, duplicate 0.358 0.021

Top 20 down-regulated genes from 3 microarray analysis from MCF-7 cells (T: with, C: without 100µM indole-3-carbinol)

Wang, Kim and MilnerAACR 2002

Cover et al. Cancer Research 59:1244, 1999.

Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells

M Tamoxifen

Inte

grat

ed

De n

s it y

/Ar e

a(p

ixel

val

ue/m

m2 )

0 0.5 1

0-

20-

40-

60-

80-

100-

0

50

100

I3C (M)

Soy Intake and CancerSoy Intake and Cancer

ConcernsConcernsGrowth enhancement of human mammary tumors transplanted into mice Growth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids that were fed soy or isoflavonids (Hsieh, et al. Cancer Res. 58:3833, 1998).(Hsieh, et al. Cancer Res. 58:3833, 1998).

17 of 26 animal studies reveal soy or 17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor soybean isoflavones reduce tumor tumor developmenttumor development

19 or 21 human epidemiological studies 19 or 21 human epidemiological studies provide evidence of protection against provide evidence of protection against cancer, especially rectal and stomach cancer, especially rectal and stomach cancers (1 study reported increase)cancers (1 study reported increase)

Soymilk Intake & Prostate Cancer Risk

Cancer Causes Control 9: 553, 1998

0 <1 1 >1

Daily Intake (servings)

Re

lativ

e R

isk

1.00.9

0.8

0.3*

More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!

Caloric Restriction in Yeast causes silencing of genes and extended life span (Guarente and Kenyon Nature 2000; 408:255

Colon Cancer and Exercise

Is it Possiblethat

Bioactive Compoundsmight be

beneficial in some circumstancesand

detrimental in other?

Some Women Appear Susceptible to Flavonoids

Several flavonoids found to cause change in MLL gene on chromosome band 11q23

Associated with increased risk of infant leukemia linked to MLL gene

Some cancer patients treated with drugs that modify topoisomerase develop leukemia involving MLL gene. Ross (2000) Proc. Natl Acad. Sci. 97: 4411-4413. Strick et al. (2000) Proc. Natl Acad. Sci. 97:4790-4795

Vitamin E Inhibits Cisplatin-InducedApoptosis in MCF-7 Breast Cancer Cells.

Salganik, et al. Carcinogenesis 21: 909, 2000.

Control E CP CP+E

6 -

4 -

2 -

0 -

% A

pop

tosi

s +

*

**

Antioxidant reduces

efficacy of cisplatin

One Size Does Not Fit All!

Just when I knew all of life’s answers,They changed all the questions!!