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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 MedicineHuntington, West Virginia
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
Major fat types
C
O
OHStearic18:0
5 37911131517
Saturated fat
Monounsaturated fat
OHC12 918 16
O
Oleic (OA) 18:1n-9
Linoleic (LA)
18:2n-6
O
18
C13 12 9 OH
OHC12 9
O
18 15Linolenic(LNA) 18:3n-3
Polyunsaturated fats
Pre-clinical evidence for benefit of omega-3 fatty acids during cancer therapy
Supplementing the diet with omega-3 fatty acids may suppress the growth of existing cancers and may prevent or slow metastasis
Omega 3 fatty acids may increase the efficacy of chemo- or radiation therapy
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.
0 5 10 15 20 25 30 350
100
200
300
400
500
600
700
800
900
COCOdox
N-3N-3dox
MDA-MB 231 growth after initiation of DOX
Growth rate mm3/day ± SEM24.2 ± 1.1 3.3 ± 0.6
5.1 ± 0.4-0.1 ± 0.1
Number days after initiation of DOX
Mea
n t
um
or
size
(m
m3)
Corn oil diet
Omega 3 diet
0 10 20 300
250
500
750
20% Corn oil
19 % Fish oil19% Fish oil and ferric citrate
Beginning of DOX and ferric citrate
Phase II time of treatmentPhase I
20% Corn oil (no DOX treatment)
Diet
Growth of A549 lung cancer xenografts in nude mice
Days after initiation of fish oil diet
Mea
n tu
mor
siz
e (m
m3)
5 10 15 20
-75
-50
-25
0
25
50
75
Days after start of CPT-11
Control, no CPT-11
Corn oil, CPT-11
3% Fish oil, CPT-116% Fish oil, CPT-11M
ean
tum
or
size
(m
m3)
MCF7 Tumors
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.
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 decrease in size oftumor 12 days after radiation
Control DHA fed0
10
20
30
40
50
60
CO
CO 24
hrs p
ost r
ad n-3
n-3
24 h
rs p
ost r
ad0.0
0.5
1.0
1.5a
a,b
b,c
c
Met
aph
ase
ind
ex
Metaphase index in MDA-231 tumors of mice fed omega 6 or omega 3 diets with or without gamma irradiation
Omega 3 fatty acids may reduce cancer cachexia
Cachexia – from Greek kachexia - bad condition
General physical wasting and malnutrition
Usually associated with increasing tumor mass. Cannot be corrected by increasing food intake
Cancer cachexia
Omega 3 Omega 6
Potential mechanisms for therapeutic benefit
O x i d a t i v e S t r e s sL P S , i r r a d i a t i o n , U V , F e a n d o t h e rp r o o x i d a n t s o r c h e m o t h e r a p e u t i c d r u g s
R O S
V i t E
P P A R • c i s r e t i n o l r e c e p t o r
P e r o x i s o m eβ - o x i d a t i o n
l i p i d b i n d i n g p r o t e i n sP 4 5 0 i s o z y m e s
A O E s
P P R E sg e n e s
N u c l e u s
I κ B • N F κ B
P O 4
N F κ B
g e n e s
E P A o r A A
I L - 1I L - 6I L - 1 2M M I FT N F α
T B X 2
L T B 4
P G E 2
P G E 3
L T B 5
T B X 3
N S A I D S
A A o r E P A
p r o l i f e r a t i o ni n f l a m m a t i o n
e n h a n c e s p l a t e l e t a g g r e g a t i o np r o i n f l a m m a t o r yp r o p r o l i f e r a t i v e
a n t i i n f l a m m a t o r ya n t i p r o l i f e r a t i v er e t a r d s p l a t e l e t a g g r e g a t i o n
I κ B - P
N F κ B - R E s
C o r n o i l
F i s h o i l
P L A2 o r P L C
C O X - c y c l o o x y g e n a s eL O X - l i p o x y g e n a s e
i n d u c e
C O X 2o r
L O X
E P A
A A
Da m
a g e :L i p
i ds D a m a g e :
P r o t e i n sD N A
V i t . E
i f f r o mE P A
i f f r o mA A
a c t i v a t e
n - 3 P U F A8 - H E T E
W Y - 1 4 , 6 4 9c l o x i b r a t e
s o m e N S A I D SD H E A S
E P A
M o d e l f o r A c t i o n s o f n - 3 P U F A i n c e l l s
Free radicals
O2-Superoxide
Hydroxyl HO•
Hydroperoxyl HO2•
Hydrogen peroxide H2O2
Lipid peroxide LO2H
Reactive nitrogen speciesThiyl
Membranes
Mitochondria
Enzymes
ChromosomesDNA
Scientific American, Dec. 1992
Defenses from oxidative damage
Endogenous antioxidative enzymes: Superoxide dismutaseCatalaseGlutathione peroxidase
Exogenous antioxidants: Vitamin E and beta carotenesUric acid and Vitamin CMetal chelators
How could the efficacy of chemotherapy be altered without causing additional damage to normal cells?
1. Most chemotherapeutic drugs cause oxidative damage to cells.
3. Fat composition of all tissues can be altered by changing the fats content of the diet.
5. Activity of endogenous antioxidative enzymes can be altered in cells.
A h i g h e r a c t i v i t y o f S O D a n d l o w e r a c t i v i t y o f G P X w o u l d r e s u l t i n t h ea c c u m u l a t i o n o f H 2 O 2 . I f c a t a l a s e i s n o t i n c r e a s e d , a c c u m u l a t e d H 2 O 2
c o u l d r e a c t w i t h F e 2 t o y i e l d h i g h l y r e a c t i v e O H a n d O H + F e 3 .··
P r o d u c t o fr e s p i r a t o r yc h a i n
O 2· -
G S H 2 G S H
S O DH 2 O 2
F e 2 O H + O H + F e 3· ·G P X
2 H 2 0
G S S G
0
10
20
A
B B
No
spec
ime
n
(me
an±
SE
M u
nits
/mg
pro
tein
)
0
10
20
30
40
50
0
5
10
15
0
10
20
30
No
spec
imen
(mea
n±
SEM
mm
ol H
2O2
deco
mpo
sed/
min
/mg
prot
ein)
0
50
100
150 A A
BB
0.0
2.5
5.0
7.5
Corn
oil
Corn
oil, d
oxFOC
FOC, dox
0
250
500
750
No
sp
eci
me
n
(me
an±
SE
Mµm
ol
b-N
AD
P o
xid
ize
d/g
pro
tein
)
Corn
oil
Corn
oil, d
oxFOC
FOC, dox
0
250
500
750
1000
A
A
B
B
Corn
oil
Corn
oil, d
oxFOC
FOC, dox
0
25
50
75
100
TUMOR LIVER COLON
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
DHA inhibits eicosanoid synthesis from AA(Rose and Connolly, 1999)
EPA effectively out-competes AA for COX activity(Needleman, P., 1979; Yang, P., et al., 2002)
EPA is a better substrate for COX 2 than AA. (Yang, P., et al., 2002)
O x i d a t i v e S t r e s sL P S , i r r a d i a t i o n , U V , F e a n d o t h e rp r o o x i d a n t s o r c h e m o t h e r a p e u t i c d r u g s
R O S
V i t E
P P A R • c i s r e t i n o l r e c e p t o r
P e r o x i s o m eβ - o x i d a t i o n
l i p i d b i n d i n g p r o t e i n sP 4 5 0 i s o z y m e s
A O E s
P P R E sg e n e s
N u c l e u s
I κ B • N F κ B
P O 4
N F κ B
g e n e s
E P A o r A A
I L - 1I L - 6I L - 1 2M M I FT N F α
T B X 2
L T B 4
P G E 2
P G E 3
L T B 5
T B X 3
N S A I D S
A A o r E P A
p r o l i f e r a t i o ni n f l a m m a t i o n
e n h a n c e s p l a t e l e t a g g r e g a t i o np r o i n f l a m m a t o r yp r o p r o l i f e r a t i v e
a n t i i n f l a m m a t o r ya n t i p r o l i f e r a t i v er e t a r d s p l a t e l e t a g g r e g a t i o n
I κ B - P
N F κ B - R E s
C o r n o i l
F i s h o i l
P L A2 o r P L C
C O X - c y c l o o x y g e n a s eL O X - l i p o x y g e n a s e
i n d u c e
C O X 2o r
L O X
E P A
A A
Da m
a g e :L i p
i ds D a m a g e :
P r o t e i n sD N A
V i t . E
i f f r o mE P A
i f f r o mA A
a c t i v a t e
n - 3 P U F A8 - H E T E
W Y - 1 4 , 6 4 9c l o x i b r a t e
s o m e N S A I D SD H E A S
E P A
M o d e l f o r A c t i o n s o f n - 3 P U F A i n c e l l s
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 of ras (Collett et al, 2001) and AP-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)
Functional apoptotic pathways help control cell growth
COX-2 expression downregulates apoptotic pathway (Tsujii & DuBois, 1995, Connolly & Rose, 1998)
NFκB activation blocks apoptosis (Schwartz, 1999), n-3 fatty acids block NFκB 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)
Terminally differentiated cells don’t multiply
Omega -3 fatty acids induced differentiation of breast cancer cells (Wang, 2000)
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)
Omega 3 fatty acids decrease estrogen metabolism
PGE2 activates P450 aromatase to increase estrogen production (Noble, et al. 1997)
Shift in estrogen metabolism towards 16α-hydroxylation increases the formation of aberrant hyperproliferation in breast. Omega-3 supplements decreased 16α-hydroxylation (Osborne, et al. 1988)
Summary: N-3 fatty acids may be detrimental to growth of metastatic or residual cancer cells by:
• Altering eicosanoid metabolism
• Slowing cancer cell mitosis
• Increasing cancer cell death
• Inducing differentiation
• Suppressing angiogenesis
• Altering estrogen metabolism
Clinical evidence of benefit
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. of Iowa Cancer Center
0.3 g/kg/day - 70 kg patient can consume up to 21 g/dayDose limiting toxicity was gastrointestinal, mainly diarrhea
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
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 changed composition of breast adipose tissue. Breast adipose composition changed more rapidly than gluteal adipose composition.
Epidemiology studies Simonsen et al. Am J Epidemiology 147:342, 1998
4 of 5 centers ↑n3/n6 EURAMIC = ↓breast cancer risk
Goodstein et al. J Nutr 133:1409, 2003Premenopausal ↑n3/n6 = non significant ↓breast cancer riskPostmenopausal ↑n3/n6 = significant ↓breast cancer risk
Maillard et al. Int J Cancer 98:78, 2002 ↑DHA = significant ↓breast cancer risk ↑long chain n3/n6 = significant ↓breast cancer risk
Bagga et al. Nutr Cancer 42:180, 2002N6 fat significantly higher in breast cancer casesfor a given level of n6, higher EPA or DHA were protective
Pala et al J Natl Cancer Inst 93:1088, 2001↑DHA = significant ↓breast cancer risk
Summary
• Preclinical studies indicate that n-3 fatty acids should be beneficial for cancer treatment
• Mechanistic studies indicate feasible mechanisms for the 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 cancer therapy or may reduce risk for breast cancer
Bulldoggin’ Cancer