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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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