Hard Man Omega 3

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Omega-3 fatty acids and cancer therapy

W. Elaine Hardman, Ph.D.

Department of Biochemistry and Microbiology

Marshall University School of Medicine

Huntington, West Virginia


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Outline

What are omega 3 fatty acids?

Pre-clinical evidence for benefit of n-3 fatty acids during cancer

therapy

Potential mechanisms for therapeutic benefit of n-3 fatty acids

Clinical evidence for benefit of n-3 fatty acids during cancer

therapy


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Major fat types

C

O

OHStearic

18:0

5 37911131517

Saturated fat

Monounsaturated fat

OHC12 918 16

O

Oleic(OA)

18:1n-9


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Linoleic

(LA)

18:2n-6

O

18

C13 12 9 OH

OHC12 9

O

18 15Linolenic(LNA)

18:3n-3

Polyunsaturated fats


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Pre-clinical evidence for benefit of omega-3 fatty

acids during cancer therapy

Supplementing the diet with omega-3 fatty acids maysuppress the growth of existing cancers and may prevent or

slow metastasis

Omega 3 fatty acids may increase the efficacy of chemo- or

radiation therapy


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Hormone responsive tumors such as:

breast, prostate and colon cancers

seem especially sensitive to omega 3 fatty acids.

However, in animal models, lung cancer growth has

been also slowed by omega 3 fatty acids.


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0 5 10 15 20 25 30 350

100

200

300

400

500

600

700

800900

CO

COdox

N-3

N-3dox

MDA-MB 231 growth after initiation of DOX

Growth rate mm3/day s SEM

24.2 s 1.1

3.3 s 0.6

5.1 s 0.4

-0.1 s

Number days after initiation of DOX

Meantu

morsize(mm

3) Corn oil diet

Omega 3 diet


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5 10 15 20

-75

-50

-25

0

25

50

75

Days aft r start f PT-11

Control, noCPT-11

Cornoil, CPT-11

3% Fis oil, CPT-11

6% Fis oil, CPT-11Meantu

ors

ize(

3) MCF7 Tu ors


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In animal models, the efficacies of:

epirubicin (Bougnoux),

5-fluorouracil (Hochwald),

mitomycin C (Pardini),

araC (Cha) and

tamoxifen (DeGraffenried)

have also been enhanced in the presence of an omega 3 dietary

supplement.


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Omega 3 fat may increase radiation sensitivity

of cancer cells

Irradiation reduced the size of chemically induced rat

mammary gland tumors (Colas, et al).

Percent ecrease insize ft r 12 aysafter radiati n

Control DHA fed

0

10

20

30

40

50

60


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CO

CO

24

rspost

rad

n-3

n-324

rs

postrad

0.0

0.5

1.0

1.5a

a,b

b,c

cMetaphas

e

index

Metaphase index in MDA-231 tumors of mice fed omega 6

or omega 3 diets with or without gamma irradiation


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Omega 3 fatty acids may reduce cancer cachexia

Cachexia from Greekkachexia -bad condition

General physical wasting and malnutrition

Usually associated with increasing tumor mass. Cannot

be corrected by increasing food intake


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Cancer cachexia

Omega 3 Omega 6


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Potential mechanisms for therapeutic benefit


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Oxidative StressLPS, irradiation, UV, Feandot erprooxidants orc emot erapeutic dru s

ROS

Vit E

PPARy cis retinol receptor

Peroxisome

F -oxidationlipid binding proteins

P450 isozymesAOEs

PPREsgenes

ucleus

IOByNFOB

PO4

NFOB

genes

EPAorA

A

IL-1IL-6IL-12MMIF

TNFE

T 2LT 4PGE2P E3LT 5T 3

NSAIDS

AAorEP

A

proliferationinflammation

enhances pl atelet aggregation

proinflammatory

proproliferative

antiinflammatory

antiproliferative

retards platelet aggregation

IOB-P

NFOB-REs

Cornoil

Fishoil

PLA2orP

LC

COX - cyclooxygenase

LOX - lipoxygenase

induce

COX2

orLOX

EPA

AA

Dama

ge:

Lipids

Damage:Pr teins

DNA

Vit. E

if fromEPA

if fromAA

activate

n-3PUFA8-HETE

WY -14,649clox ibrate

someNSAIDS

DHEAS

EPA

Model forActionsofn-3PUFA in cells


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Free radicals

O2-

Superoxide

Hydroxyl HOy

Hydroperoxyl HO2y

Hydrogen peroxide H2O2

Lipid peroxide LO2H

Reactive nitrogen species

Thiyl


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Membranes

Mitochondria

Enzymes

Chromosomes

DNA

Scientific American, Dec. 1992


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Defenses from oxidative damage

Endogenous antioxidative enzymes:

Superoxide dismutase

Catalase

Glutathione peroxidase

Exogenous antioxidants:

Vitamin E and beta carotenes

Uric acid and Vitamin C

Metal chelators


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How could the efficacy of chemotherapy be altered

without causing additional damage to normal cells?

1. Most chemotherapeutic drugs cause oxidative

damage to cells.

2. Fat composition of all tissues can be altered by

changing the fats content of the diet.

3. Activity of endogenous antioxidative enzymes can be

altered in cells.


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A higher a tivity of SOD and lower a tivity of GPX would result in the

a umulation of H O . If atalase is not in reased, a umulated H O

ould rea t with Fe to yield highly rea tive OH and OH + Fe3.

Produ t of

respiratoryhain

O-

GSH GSH

SODH O

Fe OH + OH + Fe3

GPXH 0

GSSG


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0

10

20

A

B B

Nos

ecimen

(meansS

EM

nits/mg

rote

in)

0

10

20

30

40

50

0

5

10

15

0

10

20

30

Nos

ecimen

(meansS

EMmmolH2

O2

decomposed

/min/mg

protein)

0

50

100

150 A A

BB

0.0

2.5

5.0

7.5

Cornoil

Cornoil,

dox

OC

OC

,dox

0

250

500

750

Nos

ecimen

(meansS

EM

Q

mol

-NAD

oxid

ized/g

rotein

)

Cornoil

Cornoil,

dox

OC

OC

,dox

0

250

500

750

1000

A

A

B

B

Cornoil

Cornoil,

dox

OC

OC

,dox

0

25

50

75

100

T MO I ER CO ON

Superoxide dismutase

Catalase

Glutathione peroxidase

Antioxidant enzyme

activity in mice fed 5%

CO or 3% FOC/2% CO

diets with or without

DOX treatment for 2 wks

o e or c ons o n- n ce s


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DHA inhibits eicosanoid

synthesis from AA(Rose and Connolly, 1999)

EPA effectively out-

competes AA for COXactivity(Needleman, P., 1979; Yang, P., et al.,

2002)

EPA is a better substratefor COX 2 than AA.(Yang, P., et al., 2002)

xidati e Stressdiation, , e and othernts or chemotherapeutic drugs

ROS

Vit E

PPARy cis retinol receptor

eroxisome

-oxidation

lipid inding proteins450 isozymes

AOEs

PPREsgenes

Nucleus

IOByNFOB

PO4

NFOB

genes

EPAorA

A

I -1I -6

I -12MMI

TNFE

TBX2TB4

PGE

PGE3TB5

TBX3

NSAIDS

AAor

EPA

proliferation

inflammation

enhances platelet aggregation

proinflammatory

proproliferati e

antiinflammatory

antiproliferati e

retards platelet aggregation

IOB-P

NFOB-REs

Corn oil

ish oil

PLA

2orPLC

COX - cyclooxygenase

induce

COX

orLOX

EPA

AA

Dam

age:

ipid

s Damage:Proteins

DNA

Vit. E

if fromEPA

if fromAA

acti ate

PUFA8-HETE

Y-14,649

lox i rate

NSAIDS

DHEAS

o e or c ons o n- n ce s


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Residual cancer cells must multiply for the tumor

to reoccur or for metastatic sites to grow

LA and AA activate PKC stimulating mitosis (Hannun et al.,1986)

N-3 fatty acids decrease activity ofras (Collett et al, 2001) andAP-1 (Liu, et al., 2001)

AA products of COX and LOX increase mitosis; EPA and

DHA decreased mitosis and inhibited growth of breast and

colon cancer cells (Rose & Connolly, 1990; Buckman, 1991; Abou-El-Ela, 1989)


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Functional apoptotic pathways help

control cell growth

COX-2 expression downregulates apoptotic pathway (Tsujii &DuBois, 1995, Connolly & Rose, 1998)

NFOB activation blocks apoptosis (Schwartz, 1999), n-3 fatty

acids blockNFOB activation

DHA inactivated Bcl-2 family genes and increased transcription

of genes and transcription factors that induce apoptosis(Narayanan, et al, 2001; Chiu, et al., 1999)


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Terminally differentiated cells dont multiply

Omega -3 fatty acids induced differentiation of breast cancer

cells (Wang, 2000)


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Angiogenesis must occur for tumors to grow

and metastasize

n-6 products of COX-2 and 12-LOX stimulate angiogenesis,

n-3 products do not(Form & Auerback, 1983; Connolly & Rose, 1998)


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Omega 3 fatty acids decrease estrogen metabolism

PGE2 activates P450 aromatase to increase estrogen

production (Noble, et al. 1997)

Shift in estrogen metabolism towards 16E-hydroxylation

increases the formation of aberrant hyperproliferation in

breast. Omega-3 supplements decreased 16E-hydroxylation(Osborne, et al. 1988)


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Summary:

N-3 fatty acids may be detrimental to growth ofmetastatic or residual cancer cells by:

Altering eicosanoid metabolism

Slowing cancer cell mitosis

Increasing cancer cell death

Inducing differentiation

Suppressing angiogenesis

Altering estrogen metabolism


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Clinical evidence of benefit


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Maximum tolerated dose

Burns, et al. Phase I clinical study of fish oil fatty acid

capsules for patients with cancer cachexia: cancer and

leukemia group B study 9473. Clin Cancer Res. 5:3842,

1999

Univ. ofIowa Cancer Center

0.3 g/kg/day - 70 kg patient can consume up to 21 g/day

Dose limiting toxicity was gastrointestinal, mainly diarrhea


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Effects on cachexia

Barber, Fearon, Tisdale (Dept of Surgery, Univ of Edinburgh)

Various papers on cachexia in pancreatic cancer patients

EPA supplement improved life span in pancreatic cancer

patients even with no other treatment

Patients consuming an n-3 containing supplement gained

weight and quality of life was improved

Patients excreted less IL-6 and less proteolysis inducing

factor


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Breast cancer

Bougnoux (Univ Tours) localized breast carcinoma

patients with higher levels of DHA in breast adipose tissue

responded better to chemotherapy. Level of n-3 fatty acids

was higher in patients with complete or partial remission

than in patients with no response or tumor progression(p < 0.004)

Bagga (UCLA School of Medicine) consumption of an n-

3 supplement for 3 months significantly changedcomposition of breast adipose tissue. Breast adipose

composition changed more rapidly than gluteal adipose

composition.


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Epidemiology studiesSimonsen et al. Am J Epidemiology 147:342, 1998

4 of 5 centers on3/n6 EURAMIC = qbreast cancer risk

Goodstein et al. J Nutr 133:1409, 2003

Premenopausalon3/n6 = non significant qbreast cancer risk

Postmenopausalon3/n6 = significant qbreast cancer risk

Maillard et al. Int J Cancer 98:78, 2002oDHA = significant qbreast cancer risk

olong chain n3/n6 = significant qbreast cancer risk

Bagga et al. Nutr Cancer 42:180, 2002

N6 fat significantly higher in breast cancer cases

for a given level of n6, higher EPA or DHA were protective

Pala et al J Natl CancerInst 93:1088, 2001

oDHA = significant qbreast cancer risk


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Summary

Preclinical studies indicate that n-3 fatty acids should

be beneficial for cancer treatment

Mechanistic studies indicate feasible mechanisms forthe influence of n-3 fatty acids on tumor growth,

survival and response to chemotherapy

Limited clinical studies that are available indicate that

n-3 fatty acids have been beneficial during cancertherapy or may reduce risk for breast cancer


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