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A Higher Dietary Ratio of Long-Chain Omega-3 to
Total Omega-6 Fatty Acids for Prevention of COX-2-
James J. DiNicolantonioa, Mark F. McCartyb, Subhankar Chatterjeec, Carl J. Lavied & James
a Mid America Heart Institute at Saint Luke's Hospital, Kansas City, Missouri, USA
b Catalytic Longevity, Carlsbad, California, USA
c R. G. Kar Medical College & Hospital, Kolkata, India
d John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of
Queensland School of Medicine, New Orleans, Louisiana, USA and Pennington Biomedical
Research Center, Baton Rouge, Louisiana, USA
e Mid America Heart Institute at Saint Luke's Hospital, Kansas City, Missouri, USA and
University of Missouri-Kansas City, Kansas City, Missouri, USA
Published online: 30 Oct 2014.
To cite this article: James J. DiNicolantonio, Mark F. McCarty, Subhankar Chatterjee, Carl J. Lavie & James H. O’Keefe
(2014): A Higher Dietary Ratio of Long-Chain Omega-3 to Total Omega-6 Fatty Acids for Prevention of COX-2-Dependent
Adenocarcinomas, Nutrition and Cancer, DOI: 10.1080/01635581.2014.956262
To link to this article: http://dx.doi.org/10.1080/01635581.2014.956262
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A Higher Dietary Ratio of Long-Chain Omega-3 to Total
Omega-6 Fatty Acids for Prevention of COX-2-Dependent
James J. DiNicolantonio
Mid America Heart Institute at Saint Luke’s Hospital, Kansas City, Missouri, USA
Mark F. McCarty
Catalytic Longevity, Carlsbad, California, USA
R. G. Kar Medical College & Hospital, Kolkata, India
Carl J. Lavie
John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland
School of Medicine, New Orleans, Louisiana, USA and Pennington Biomedical Research Center, Baton
Rouge, Louisiana, USA
James H. O’Keefe
Mid America Heart Institute at Saint Luke’s Hospital, Kansas City, Missouri, USA and University
of Missouri-Kansas City, Kansas City, Missouri, USA
Compelling evidence that daily low-dose aspirin decreases risk
for a number of adenocarcinomas likely reﬂects the fact that a
modest but consistent inhibition of cyclooxygenase-2 (COX-2)
activity can have a meaningful protective impact on risk for such
cancers. The cancer-promoting effects of COX-2 are thought to
be mediated primarily by prostaglandin E2 (PGE2), synthesized
from arachidonic acid. The long-chain omega-3s eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), abundant in many
fatty ﬁsh, can interfere with the availability of arachidonate to
COX-2 by multiple complementary mechanisms; moreover, the
PGE3 produced by COX-2 from EPA is a competitive inhibitor of
the receptors activated by PGE2. These considerations have given
rise to the hypothesis that a high dietary intake of EPA/DHA,
relative to omega-6 (from which arachidonate is generated),
should lessen risk for a number of adenocarcinomas by impeding
PGE2 production and activity—while not posing the risk to
vascular health associated with COX-2-speciﬁc nonsteroidal
antiinﬂammatory agents. Analyses that focus on studies in which
the upper category of ﬁsh consumption (not fried or salt-
preserved) is 2 or more servings weekly, and on studies that
evaluate the association of long-term ﬁsh oil supplementation
with cancer risk yields a number of ﬁndings that are consistent
with the hypothesis. Further studies of this nature may help to
clarify the impact of adequate regular intakes of long-chain
omega-3 on cancer risk, and perhaps provide insight into the
dose-dependency of this effect.
There is considerable evidence that cyclooxygenase-2
(COX-2) activity often plays a mediating role in the induction
and progression of a range of cancers, most notably adenocar-
cinomas (1–8). Epidemiology correlating regular nonsteroidal
anti-inﬂammatory drug use with decreased risk for various
adenocarcinomas is consistent with this proposition (9). Yet,
the most compelling evidence in this regard is a meta-analysis
by Rothwell and colleagues examining cancer mortality in
subjects randomized to receive daily aspirin for at least 4 yr in
8 large clinical trials originally designed to assess aspirin’s
impact on cardiovascular events (10). Deaths attributed to can-
cer were recorded in each of these trials, and for 3 of these tri-
als a follow up of 20 yr was achieved. The impact of aspirin
assignment on total mortality from solid cancers during at least
10 years of follow-up was dramatic—cancers death were
Submitted 22 December 2013; accepted in ﬁnal form 27 July 2014.
Address correspondence to James J. DiNicolantonio, Saint Luke’s
Mid America Heart Institute, 4321 Washington Street, Suite 2100,
Kansas City, MO 64111. E-mail: email@example.com
Nutrition and Cancer, 0(0), 1–6
Copyright Ó2014, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
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roughly 25% lower in comparison to subjects who received
placebo [hazard Ratio (HR) D0.75, 95% conﬁdence interval
(CI): 0.67–0.84, P<.0001, among patients followed for
20 yr]. This beneﬁt primarily reﬂected lower deaths from
adenocarcinomas of gastrointestinal or non-gastrointestinal
origin, which were about a third less likely over 20 yr in those
randomized to aspirin. Cancer sites in which prevention of
cancer death reached statistical signiﬁcance included esoph-
ageal, colorectal, pancreatic, and lung; the protection afforded
from lung and esophageal cancers was speciﬁc to adenocarci-
nomas. A trend toward prevention of prostate cancer deaths
over 20 yr did not achieve statistical signiﬁcance (HR D0.83,
95% CI: 0.61–1.06, PD0.12). Unfortunately, owing to the
fact that the large majority of subjects enrolled in these trials
were male, information on female-speciﬁc cancers was sparse
and was not reported.
As might be expected, this effect showed considerable
latency, with signiﬁcant cancer prevention not emerging until
over 5 years of follow-up. Also in line with expectation, those
asked to take aspirin for at least 7.5 yr achieved greater long-
term cancer prevention than those taking aspirin for shorter
periods. Remarkably, no dose-dependency was observed—
75 mg aspirin daily was found to be as protective as higher
Aspirin’s capacity to inhibit cyclooxygenase activity, even
in doses as low as 75 mg daily, reﬂects the fact that it causes
permanent inhibition of this enzyme (both COX-1 and COX-
2) by inducing covalent acetylation of its active site (11).
There is good reason to suspect that the inhibition of COX-2
in preneoplastic lesions or early cancers was primarily respon-
sible for the protective beneﬁt reported by Rothwell et al.
(10). Previous epidemiological analyses focusing speciﬁcally
on colorectal cancer have found that regular aspirin use
reduces risk for, and death from, colorectal cancers that
express COX-2; no impact of aspirin was found on the occur-
rence or clinical course of colorectal cancers lacking COX-2
(12,13). It is unlikely that aspirin’s ability to inhibit platelet
aggregation via COX-1 inhibition could have been responsible
for prevention of cancer mortality, because the Women’s
Health Study, in which subjects received 100 mg aspirin every
other day, failed to ﬁnd any impact on cancer incidence or
mortality during 10 years of follow up (14)—and yet such a
regimen is sufﬁcient for effective platelet stabilization. [Anal-
ogously, 325 mg aspirin every other day failed to inﬂuence
colorectal cancer risk in the Physicians’ Health Study (15).] In
concert with the ample evidence that COX-2 often plays a key
role in the genesis and progression of cancer—notably adeno-
carcinomas—these considerations strongly suggest that COX-
2, either in transformed cells or adjoining stroma, is the key
target of aspirin’s cancer protective activity.
It can be concluded that COX-2-derived prostanoids play a
key role in driving the genesis and progression of human
adenocarcinomas. Considerable evidence indicts prostaglandin
E2 (PGE2) as the most prominent mediator in this regard. Via
activation of membrane receptors—of four isotypes, EP1–
EP4—it can exert autocrine and paracrine effects that work in
a variety of complementary ways to aid the survival and
spread of neoplastic or pre-neoplastic lesions (16–26). In vari-
ous cancers, activation of these receptors has been reported to
oppose apoptosis by such effects as increased Bcl-2 expres-
sion, decreased expression of pro-apoptotic Bax or Bim, inhib-
itory Bad phosphorylation, and Akt activation; inhibition of
apoptosis in initiated preneoplastic cells is a key mechanism
whereby cancer promoters increase cancer risk (27). These
receptors can also promote proliferation and invasive spread
in certain cancers, promote angiogenesis, and inhibit the can-
cer-killing efﬁcacy of cytotoxic T cells as well as natural killer
cells. Furthermore, in breast tissue, COX-2/PGE2 activity, act-
ing via EP2/EP4 and cyclic AMP, promotes induction of aro-
matase in stroma and in breast cancer cells (28–31); breast
stromal aromatase activity is believed to be a key determinant
of risk for estrogen-positive breast cancer post-menopausally.
AN ALTERNATIVE STRATEGY FOR SUPPRESSING COX-2
ACTIVITY: INCREASING OMEGA-3 INTAKE
As is well known, strong and persistent inhibition of COX-
1 commonly leads to gastrointestinal bleeding and nephropa-
thy. Aspirin has a higher afﬁnity for COX-1 than for COX-2,
and yet most people tolerate low-dose aspirin well. This evi-
dently reﬂects the fact that such regimens achieve only a very
partial and transitory inhibition of COX-1, and hence also of
COX-2. Unfortunately, it is now known that strong speciﬁc
inhibition of COX-2 is attended by an elevation of cardiovas-
cular risk that would be unacceptable in the general population
(34). Nonetheless, as adjuncts or alternatives to low-dose aspi-
rin, various safe measures with potential for limiting COX-2
expression can be expected to have utility for cancer preven-
tion, as reviewed recently (35). Thus, in certain cancer-prone
epithelia, induction of COX-2 can be opposed by high-normal
vitamin D status, agents which downregulate oxidative stress
(such as phase 2 inducer dietary phytochemicals and possibly
spirulina), soy isoﬂavones (via activation of estrogen receptor-
beta), and measures that decrease systemic IGF-I bioactivity,
such as quasivegan diets and active lifestyles that promote
leanness and muscle insulin sensitivity (35). In addition, meas-
ures that modulate COX-2’s access to its key substrate, arachi-
donic acid, can be expected to inﬂuence cancer induction and
The long-chain omega-3 fatty acids eicosapentaenoic acid
(EPA, 20:5n3) and docosahexaenoic acid (DHA, 22:6n3),
richly supplied by many fatty ﬁsh, can act to displace arachi-
donic acid from membrane phospholipids, in part because they
compete for the desaturase enzymes which generate arachido-
nate from linoleic acid (36–39). In addition, EPA and DHA
can act as a competitive inhibitors of arachidonate’s binding to
the active site of COX-2, and EPA acts as an alternative
2J. J. DINICOLANTONIO ET AL.
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substrate for this enzyme (40). The prostanoid PGE3 derived
from COX-2’s action on EPA not only fails to activate PGE2’s
receptors, but also acts as a competitive inhibitor in this regard
(41). Other prostanoids that EPA or DHA can give rise to tend
to have antiinﬂammatory effects, in marked contrast to the
often proinﬂammatory impacts of arachidonate products (42).
The membrane content of arachidonic acid can also be
decreased by minimizing dietary intakes of omega-6 fatty
acids, which can give rise to arachidonate by desaturation and
elongation reactions, and by minimizing intake of preformed
arachidonate (as with plant-based food choices). Hence, it is
reasonable to predict that a diet rich in EPA/DHA, although
relatively low in omega-6 fatty acids (including arachidonic
acid), could decrease the cancer-supportive activity of COX-2
by limiting its access to arachidonic acid. A corollary of this is
that—other factors being equal—such a diet could be expected
to provide protection from a range of adenocarcinomas. A
summary of the mechanisms whereby long-chain omega-3s
can oppose COX-2 activity is offered in Table 1.
Such a prediction, of course, omits from consideration the
possibility that the omega-3/omega-6 ratio of the diet might
act in ways other than modulation of COX-2 activity to inﬂu-
ence cancer induction and spread. Because omega-3-derived
mediators tend to have antiinﬂammatory actions, it perhaps is
reasonable to expect that any ancillary effects of omega-3
nutrition will more likely be protective than harmful with
respect to cancer risk. Nonetheless, it clearly is appropriate to
examine the epidemiological evidence pertinent to the propo-
sition that a relatively high dietary omega-3/omega-6 ratio can
provide protection from adenocarcinomas. Moreover, epide-
miology may provide some insight into the dose-dependency
of any protection afforded by long-chain omega-3s.
It seems reasonable to suspect that EPA/DHA intakes of at
least several grams daily, in the context of modern diets that
are typically laced with omega-6-rich oils, would be required
to have a functionally signiﬁcant impact on eicosanoid produc-
tion. In this regard, a recent placebo-controlled study demon-
strating that 2 g EPA daily could reduce polyp number and
size in patients with familial adenomatous polyposis, to an
extent similar to that seen with COX-2 inhibitors, may provide
insight regarding the omega-3 intake that might be useful for
prevention of adenocarcinomas (43). Also illuminating is a set
of studies demonstrating that ingestion of 4.4 g of ﬁsh oil
omega-3s per day can slow epithelial proliferation and PGE2
release from rectal biopsy specimens ex vivo—but not if a diet
rich in omega-6 is ingested concurrently (44,45). It is notable
that the average daily American intake of EPA CDHA is said
to be only about 100 mg (46). The proposition that EPA and/
or DHA have cancer-preventive potential can only be assessed
fairly on epidemiological studies which quantify cancer risk in
subjects who consume fatty ﬁsh multiple times weekly, and/or
that supplement with signiﬁcant doses of ﬁsh oil on a daily
basis, in the context of a diet of moderate omega-6 content.
One would not expect meta-analyses incorporating studies
from low-omega-3-intake populations to conﬁrm this
PERTINENT EPIDEMIOLOGICAL DATA
The impact of omega-3 consumption on cancer risk can be
appropriately evaluated in Italy, where the staple oil used in
cooking and as salad dressing, olive oil, is quite low in omega-
6 (about 12%), and ﬁsh is a staple food for a signiﬁcant propor-
tion of the population. In this regard, a summary of case-con-
trol studies conducted in northern Italy between 1983 and
1996 is particularly illuminating (47). Among the 7,990
patient controls employed in these studies, 23% ate ﬁsh at least
2 times weekly. Subjects who consumed ﬁsh at least 2 times
weekly, as compared to those who ate ﬁsh less than once a
week, were found to be at signiﬁcantly lower risk for ovarian
[odds ratio (OR) D0.7), endometrial (OR D0.8), pharyngeal
(OR D0.5), esophageal (OR D0.6), gastric (O R D0.7),
colonic (OR D0.6), rectal (OR D0.5), and pancreatic (OR D
0.7) cancers. No apparent protection was seen for breast or
prostate cancers. Although this report did not specify the his-
tology of the cancers observed, it can be presumed that a high
proportion of the cancers for which ﬁsh-related protection was
observed were adenocarcinomas.
A search for other epidemiological studies in which the top
category of ﬁsh consumption was two or more servings weekly
yielded a Swedish case-control study in which fatty ﬁsh con-
sumption in the upper intake group, relative to the lowest
intake group (median 0.2 servings weekly), was associated
with a signiﬁcantly lower risk for endometrial cancer: multi-
variate OR D0.6, 95% CI: 0.5–0.8; Pfor trend, 0.0002 (48).
In contrast, consumption of lean ﬁsh was not associated with
risk. In a Polish case-control study, focusing on colorectal can-
cer, the upper intake group was deﬁned as over 2 servings
weekly, and marked protection was observed: adjusted OR D
0.56; 95% CI: 0.39–0.86; a lesser but still signiﬁcant degree of
protection was seen in those eating 1–2 ﬁsh servings weekly
The Swedish study raises the point that the nature of ﬁsh—
whether or not it is fatty—and the way in which ﬁsh is pre-
served or cooked, can skew the outcomes of epidemiological
How long-chain omega-3 opposes Cox-2 activity
Competition for desaturase enzymes which convert linoleic
acid to arachidonic acid (37,38)
Competition with arachidonate for incorporation into
membrane phospholipids (36)
Competition with arachidonate for access to the active site of
PGE3, synthesized from EPA, acts as a competitive inhibitor
of PGE2 receptors for EP2/EP4 (41)
OMEGA-3/OMEGA-6 RATIO, COX-2, AND ADENOCARCINOMAS 3
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studies evaluating ﬁsh consumption. Salt-preserved ﬁsh (as
opposed to fresh or frozen) is commonly consumed in many
cultures and may be laced with mutagens (50,51); hence, some
studies ﬁnd a positive association between consumption of
such ﬁsh and risk for cancers, particularly those of the upper
gastrointestinal tract (52–56). Fried ﬁsh, as opposed to baked
or boiled ﬁsh, fails to associate with protection in some stud-
ies, or is even associated with increased risk (55,57–60) frying
can reduce the total omega-3 content, while notably increasing
the omega-6/omega-3 ratio of the ﬁsh, particularly if a polyun-
saturated oil is employed (61,62). Moreover, high-temperature
cooking of ﬁsh, such as frying, can promote production of
mutagenic heterocyclic amines, as it does in other ﬂesh foods
(owing to reactions involving creatine) (63–66). In the VITa-
mins And Lifestyle (VITAL) study (cited below), nonfried ﬁsh
consumption was associated with reduced risk for pancreatic
cancer (0.62; 95% CI: 0.40, 0.98; P-trend D0.08), but con-
sumption of fried ﬁsh did not associate with protection (60).
Farmed ﬁsh, such as much marketed tilapia and salmon, tend
to have a higher omega-6/omega-3 ratio than wild ﬁsh, as they
are often fed with grains; the long-chain omega-3s in ﬁsh are
not synthesized de novo but rather stem from unicellular
organisms at the base of their natural food chain (67–69).
Hence, studies examining populations in which habitual ﬁsh
intake is low, lean, or farmed ﬁsh is preferred, or in which con-
sumption of salt-preserved or fried ﬁsh is common, may not be
appropriate for evaluating the impact of long-chain omega-3
intake on cancer risk. These considerations are summarized in
FISH OIL SUPPLEMENTATION AND CANCER RISK
Another approach to evaluating the potential of omega-3 to
decrease cancer risk—which overcomes these obstacles—is to
examine risk for adenocarcinomas in individuals who have
consumed ﬁsh oil capsules on a regular basis for years.
Although a raft of epidemiological studies have attempted to
correlate ﬁsh consumption—which tends to be sporadic—with
cancer risks, very few to date have examined regular ﬁsh oil
supplementation—which can readily provide 1 or more grams
of long-chain omega-3 daily—as a correlate of cancer risk.
This approach was taken recently by Kantor and colleagues,
using data from the prospective VITAL study, which queried
68,109 Washington residents, aged 50–76, on their lifestyle
habits, including diet and supplement usage, in 2000–2002
(70). These researchers focused on a group of subjects who
claimed to have used ﬁsh oil supplements at least 4 days a wk
for at least 3 yr. In comparison to subjects in the trial who did
not supplement with ﬁsh oil, the ﬁsh oil users were found to be
at notably lower subsequent risk for colorectal cancer (HR D
0.51, 95% CI: 0.26–1.00) after multivariate adjustments that
included an estimate of omega-6 consumption (adjustment for
only age and sex also observed protection: HR D0.48, 95%
In another analysis of the VITAL cohort, current use of ﬁsh
oil supplements was associated with reduced breast cancer
risk: HR D0.68, 95% CI: 0.50–0.92, after multivariate adjust-
ment (71). Assessed 10-yr average use of ﬁsh oil supplements
showed a trend toward protection (Ptrend D0.09). An analy-
sis of prostate cancer risk in this population failed to observe
any correlation with ﬁsh oil use (OR D0.98) (72). A recent
analysis of an Icelandic cohort, however, reported that ﬁsh oil
supplementation during later life was associated with a marked
reduction in risk for advanced prostate cancer: HR D0.43,
95% CI: 0.19–0.95 (73). These ﬁndings are actually in reason-
able accord with a meta-analysis of ﬁsh consumption and pros-
tate cancer; whereas ﬁsh consumption did not clearly associate
with incidence of prostate cancer (it emerged as protective in
case-control studies, but not in prospective cohort studies), it
was associated with a highly signiﬁcant 63% reduction in risk
for prostate cancer mortality (74). With respect to endometrial
cancer, a recent case-control study in Connecticut found that
ﬁsh oil consumption was associated with a signiﬁcantly lower
risk after multivariate adjustment: OR D0.63, 95% CI:
Very recently, a further analysis of the VITAL cohort has
appeared, focusing on global mortality, including total cancer
mortality. Total daily intake of EPA CDHA from both diet
and supplements was associated inversely with total mortality;
comparing the fourth with the ﬁrst quartile, and adjusting for
multiple potentially confounding variables, including arachi-
donic acid intake, HR D0.82, 95% CI: 0.73, 0.93. An inverse
association between omega-3 intake and total cancer mortality
was also observed: HR D0.77, 95% CI: 0.64, 0.92 (76). The
cogency of these ﬁndings may reﬂect the fact that total omega-
3 intake, from both diet and supplements, was assessed.
Additional studies examining cohorts in which a signiﬁcant
fraction of subjects are heavy regular consumers of fatty ﬁsh
(not fried or salt-preserved), or regular users of ﬁsh oil supple-
ments, preferably correcting for concurrent intake of omega-6
fats, may give us further insight into the potential of ﬁsh oil
consumption to prevent adenocarcinomas, and perhaps also
Why many epidemiological studies fail to correlate ﬁsh intake
with reduced cancer risk
Relatively low ﬁsh intake among the high-intake category
High concurrent intake of omega-6-rich oils
Predominant consumption of lean ﬁsh, low in omega-3
Farmed ﬁsh, such as tilapia, often has a relatively high omega-
6/omega-3 ratio (67–69)
Salted/preserved ﬁsh often contain mutagens such as
Fried ﬁsh has an increased omega-6/omega-3 ratio (61,62)
Fish cooked at high heat (e.g., frying) has heterocyclic amines
and other mutagens (63–66)
4J. J. DINICOLANTONIO ET AL.
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the dose-dependency of such an effect. In addition, the ran-
domized placebo-controlled Vitamin D and Omega-3 Trial,
which plans to follow 20,000 middle-aged US men and
women, half of whom will receive a supplement providing 1 g
of EPACDHA daily, for 5 yr, may offer a useful assessment
of the cancer preventive potential of ﬁsh oil, in a modest but
consistent daily dose (77).
1. Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, et al.:
Cyclooxygenase-2 and gastric carcinogenesis. APMIS 111, 915–925,
2. Piazuelo E, Jimenez P, and Lanas A: COX-2 inhibition in esophagitis,
Barrett’s esophagus and esophageal cancer. Curr Pharm Des 9,
3. Glover JA, Hughes CM, Cantwell MM, and Murray LJ: A systematic
review to establish the frequency of cyclooxygenase-2 expression in nor-
mal breast epithelium, ductal carcinoma in situ, microinvasive carcinoma
of the breast and invasive breast cancer. Br J Cancer 105, 13–17, 2011.
4. Hoellen F, Kelling K, Dittmer C, Diedrich K, Friedrich M, et al.: Impact
of cyclooxygenase-2 in breast cancer. Anticancer Res 31, 4359–4367,
5. Ohno S, Ohno Y, Suzuki N, Inagawa H, Kohchi C, et al.: Multiple roles
of cyclooxygenase-2 in endometrial cancer. Anticancer Res 25,
6. Kraus S, Naumov I, and Arber N: COX-2 active agents in the chemopre-
vention of colorectal cancer. Recent Results Cancer Res 191, 95–103,
7. Sandler AB and Dubinett SM: COX-2 inhibition and lung cancer. Semin
Oncol 31, 45–52, 2004.
8. Hussain T, Gupta S, and Mukhtar H: Cyclooxygenase-2 and prostate car-
cinogenesis. Cancer Lett 191, 125–135, 2003.
9. Moran EM: Epidemiological and clinical aspects of nonsteroidal anti-
inﬂammatory drugs and cancer risks. J Environ Pathol Toxicol Oncol 21,
10. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, et al.: Effect
of daily aspirin on long-term risk of death due to cancer: analysis of indi-
vidual patient data from randomised trials. Lancet 377, 31–41, 2011.
11. Tosco P and Lazzarato L: Mechanistic insights into cyclooxygenase irre-
versible inactivation by aspirin. ChemMedChem 4, 939–945, 2009.
12. Chan AT, Ogino S, and Fuchs CS: Aspirin and the risk of colorectal can-
cer in relation to the expression of COX-2. N Engl J Med 356,
13. Chan AT, Ogino S, and Fuchs CS: Aspirin use and survival after diagno-
sis of colorectal cancer. JAMA 302, 649–658, 2009.
14. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, et al.: Low-dose
aspirin in the primary prevention of cancer: the Women’s Health Study: a
randomized controlled trial. JAMA 294, 47–55, 2005.
15. Sturmer T, Glynn RJ, Lee IM, Manson JE, Buring JE, et al.: Aspirin use
and colorectal cancer: post-trial follow-up data from the Physicians’
Health Study. Ann Intern Med 128, 713–720, 1998.
16. Chun KS, Akunda JK, and Langenbach R: Cyclooxygenase-2 inhibits
UVB-induced apoptosis in mouse skin by activating the prostaglandin E2
receptors, EP2 and EP4. Cancer Res 67, 2015–2021, 2007.
17. Chu AJ, Chou TH, and Chen BD: Prevention of colorectal cancer using
COX-2 inhibitors: basic science and clinical applications. Front Biosci 9,
18. Wu T, Leng J, Han C, and Demetris AJ: The cyclooxygenase-2 inhibitor
celecoxib blocks phosphorylation of Akt and induces apoptosis in human
cholangiocarcinoma cells. Mol Cancer Ther 3, 299–307, 2004.
19. Mutoh M, Takahashi M, and Wakabayashi K: Roles of prostanoids in
colon carcinogenesis and their potential targeting for cancer chemopre-
vention. Curr Pharm Des 12, 2375–2382, 2006.
20. Wang D and DuBois RN. Cyclooxygenase-2: a potential target in breast
cancer. Semin Oncol 31, 64–73, 2004.
21. Wendum D, Masliah J, Trugnan G, and Flejou JF: Cyclooxygenase-2 and
its role in colorectal cancer development. Virchows Arch 445, 327–333,
22. Dempke W, Rie C, Grothey A, and Schmoll HJ: Cyclooxygenase-2: a
novel target for cancer chemotherapy? J Cancer Res Clin Oncol 127,
23. Greenhough A, Wallam CA, Hicks DJ, Moorghen M, Williams AC, et al.:
The proapoptotic BH3-only protein Bim is downregulated in a subset of
colorectal cancers and is repressed by antiapoptotic COX-2/PGE(2) sig-
nalling in colorectal adenoma cells. Oncogene 29, 3398–3410, 2010.
24. Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, et al.:
Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an
in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res 2,
25. Lin DW and Nelson PS. The role of cyclooxygenase-2 inhibition for the
prevention and treatment of prostate carcinoma. Clin Prostate Cancer 2,
26. Sun Y, Tang XM, Half E, Kuo MT, and Sinicrope FA: Cyclooxygenase-2
overexpression reduces apoptotic susceptibility by inhibiting the cyto-
chrome c-dependent apoptotic pathway in human colon cancer cells. Can-
cer Res 62, 6323–6328, 2002.
27. Schulte-Hermann R, Bursch W, Kraupp-Grasl B, Oberhammer F, and
Wagner A. Programmed cell death and its protective role with particular
reference to apoptosis. Toxicol Lett 64–65, 569–574, 1992.
28. Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, et al.:
Correlation of aromatase and cyclooxygenase gene expression in human
breast cancer specimens. Cancer Lett 140, 27–35, 1999.
29. Diaz-Cruz ES, Shapiro CL, and Brueggemeier RW: Cyclooxygenase
inhibitors suppress aromatase expression and activity in breast cancer
cells. J Clin Endocrinol Metab 90, 2563–2570, 2005.
30. Subbaramaiah K, Hudis C, Chang SH, Hla T, and Dannenberg AJ: EP2
and EP4 receptors regulate aromatase expression in human adipocytes
and breast cancer cells. Evidence of a BRCA1 and p300 exchange. J Biol
Chem 283, 3433–3444, 2008.
31. Subbaramaiah K, Morris PG, Zhou XK, Morrow M, Du B, Get al.:
Increased levels of COX-2 and prostaglandin E2 contribute to elevated
aromatase expression in inﬂamed breast tissue of obese women. Cancer
Discov 2, 356–365, 2012.
32. Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, et al.: Obe-
sity is associated with inﬂammation and elevated aromatase expression in
the mouse mammary gland. Cancer Prev Res (Phila) 4, 329–346, 2011.
33. Rose DP and Vona-Davis L: Biochemical and molecular mechanisms for
the association between obesity, chronic inﬂammation, and breast cancer.
Biofactors 40, 1–12, 2013.
34. Martinez-Gonzalez J and Badimon L: Mechanisms underlying the cardio-
vascular effects of COX-inhibition: beneﬁts and risks. Curr Pharm Des
13, 2215–2227, 2007.
35. McCarty MF: Minimizing the cancer-promotional activity of cox-2 as a
central strategy in cancer prevention. Med Hypotheses 78, 45–57, 2012.
36. Fragiskos B, Chan AC, and Choy PC: Competition of n-3 and n-6 polyun-
saturated fatty acids in the isolated perfused rat heart. Ann Nutr Metab 30,
37. Garg ML, Sebokova E, Thomson AB, and Clandinin MT: Delta 6-desa-
turase activity in liver microsomes of rats fed diets enriched with choles-
terol and/or omega 3 fatty acids. Biochem J 249, 351–356, 1988.
38. Gronn M, Christensen E, Hagve TA, and Christophersen BO: Effects of
dietary puriﬁed eicosapentaenoic acid (20:5 (n-3)) and docosahexaenoic
acid (22:6(n-3)) on fatty acid desaturation and oxidation in isolated rat
liver cells. Biochim Biophys Acta 1125, 35–43, 1992.
OMEGA-3/OMEGA-6 RATIO, COX-2, AND ADENOCARCINOMAS 5
Downloaded by [220.127.116.11] at 08:53 04 November 2014
39. Lands WE, Libelt B, Morris A, Kramer NC, Prewitt TE, et al.: Mainte-
nance of lower proportions of (n-6) eicosanoid precursors in phospholi-
pids of human plasma in response to added dietary (n-3) fatty acids.
Biochim Biophys Acta 1180, 147–162, 1992.
40. Vecchio AJ, Simmons DM, and Malkowski MG: Structural basis of fatty
acid substrate binding to cyclooxygenase-2. J Biol Chem 285,
41. Funahashi H, Satake M, Hasan S, Sawai H, Newman RA, et al.: Opposing
effects of n-6 and n-3 polyunsaturated fatty acids on pancreatic cancer
growth. Pancreas 36, 353–362, 2008.
42. Calder PC: n-3 fatty acids, inﬂammation and immunity: new mechanisms
to explain old actions. Proc Nutr Soc 72, 326–336, 2013.
43. West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, et al.:
Eicosapentaenoic acid reduces rectal polyp number and size in familial
adenomatous polyposis. Gut 59, 918–925, 2010.
44. Bartram HP, Gostner A, Scheppach W, Reddy BS, Rao CV, Dusel G,
Richter F, Richter A, Kasper H. Effects of ﬁsh oil on rectal cell prolifera-
tion, mucosal fatty acids, and prostaglandin E2 release in healthy subjects.
Gastroenterology 105:1317–1322, 1993.
45. Bartram HP, Gostner A, Reddy BS, Rao CV, Scheppach W, et al.: Miss-
ing anti-proliferative effect of ﬁsh oil on rectal epithelium in healthy vol-
unteers consuming a high-fat diet: potential role of the n-3:n-6 fatty acid
ratio. Eur J Cancer Prev 4, 231–237, 1995.
46. Fabian CJ and Kimler BF. Marine-derived omega-3 Fatty acids. Am Soc
Clin Oncol Educ Book 97–101, 2013.
47. Fernandez E, Chatenoud L, La VC, Negri E, and Franceschi S: Fish con-
sumption and cancer risk. Am J Clin Nutr 70, 85–90, 1999.
48. Terry P, Wolk A, Vainio H, and Weiderpass E: Fatty ﬁsh consumption
lowers the risk of endometrial cancer: a nationwide case-control study in
Sweden. Cancer Epidemiol Biomarkers Prev 11, 143–145, 2002.
49. Jedrychowski W, Maugeri U, Pac A, Sochacka-Tatara E, and Galas A:
Protective effect of ﬁsh consumption on colorectal cancer risk. Hospital-
based case-control study in Eastern Europe. Ann Nutr Metab 53,
50. Fong LY, Ho JH, and Huang DP: Preserved foods as possible cancer haz-
ards: WA rats fed salted ﬁsh have mutagenic urine. Int J Cancer 23,
51. Stich HF, Chan PK, and Rosin MP: Inhibitory effects of phenolics, teas
and saliva on the formation of mutagenic nitrosation products of salted
ﬁsh. Int J Cancer 30, 719–724, 1982.
52. Gonzalez CA, Sanz JM, Marcos G, Pita S, Brullet E, et al.: Dietary fac-
tors and stomach cancer in Spain: a multi-centre case-control study. Int J
Cancer 49, 513–519, 1991.
53. Jakszyn P and Gonzalez CA. Nitrosamine and related food intake
and gastric and oesophageal cancer risk: a systematic review of
the epidemiological evidence. World J Gastroenterol 12, 4296–4303,
54. Ren ZF, Liu WS, Qin HD, Xu YF, Yu DD, et al.: Effect of family history
of cancers and environmental factors on risk of nasopharyngeal carci-
noma in Guangdong, China. Cancer Epidemiol 34, 419–424, 2010.
55. Lin Y, Ueda J, Kikuchi S, Totsuka Y, Wei WQ, et al.: Comparative epi-
demiology of gastric cancer between Japan and China. World J Gastroen-
terol 17, 4421–4428, 2011.
56. Ye WM, Yi YN, Luo RX, Zhou TS, Lin RT, et al.: Diet and gastric can-
cer: a casecontrol study in Fujian Province, China. World J Gastroenterol
4, 516–518, 1998.
57. Takezaki T, Inoue M, Kataoka H, Ikeda S, Yoshida M, et al.: Diet and
lung cancer risk from a 14-year population-based prospective study in
Japan: with special reference to ﬁsh consumption. Nutr Cancer 45,
58. Stott-Miller M, Neuhouser ML, and Stanford JL: Consumption of deep-
fried foods and risk of prostate cancer. Prostate 73, 960–969, 2013.
59. Joshi AD, John EM, Koo J, Ingles SA, and Stern MC: Fish intake, cook-
ing practices, and risk of prostate cancer: results from a multi-ethnic case-
control study. Cancer Causes Control 23, 405–420, 2012.
60. He K, Xun P, Brasky TM, Gammon MD, Stevens J, et al.: Types of
ﬁsh consumed and ﬁsh preparation methods in relation to pancreatic
cancer incidence: the VITAL Cohort Study. Am J Epidemiol 177,
61. Ansorena D, Guembe A, Mendizabal T, and Astiasaran I: Effect of ﬁsh
and oil nature on frying process and nutritional product quality. J Food
Sci 75, H62–H67, 2010.
62. Strobel C, Jahreis G, and Kuhnt K: Survey of n-3 and n-6 polyunsat-
urated fatty acids in ﬁsh and ﬁsh products. Lipids Health Dis 11,
63. Zhang XM, Wakabayashi K, Liu ZC, Sugimura T, and Nagao M: Muta-
genic and carcinogenic heterocyclic amines in Chinese cooked foods.
Mutat Res 201, 181–188, 1988.
64. Liu XL: [Genotoxicity of fried ﬁsh extract, MeIQ and inhibition by
green tea antioxidant]. Zhonghua Zhong Liu Za Zhi 12, 170–173,
65. Khan MR, Busquets R, Saurina J, Hernandez S, and Puignou L: Identiﬁ-
cation of seafood as an important dietary source of heterocyclic amines
by chemometry and chromatography-mass spectrometry. Chem Res Toxi-
col 26, 1014–1022, 2013.
66. Skog KI, Johansson MA, and Jagerstad MI: Carcinogenic heterocyclic
amines in model systems and cooked foods: a review on formation, occur-
rence and intake. Food Chem Toxicol 36, 879–896, 1998.
67. Hamilton MC, Hites RA, Schwager SJ, Foran JA, Knuth BA, et al.: Lipid
composition and contaminants in farmed and wild salmon. Environ Sci
Technol 39, 8622–8629, 2005.
68. Karapanagiotidis IT, Bell MV, Little DC, Yakupitiyage A, and Rakshit
SK: Polyunsaturated fatty acid content of wild and farmed tilapias in
Thailand: effect of aquaculture practices and implications for human
nutrition. J Agric Food Chem 54, 4304–4310, 2006.
69. Young K: Omega-6 (n-6) and omega-3 (n-3) fatty acids in tilapia and
human health: a review. Int J Food Sci Nutr 60(Suppl 5), 203–211,
70. Kantor ED, Lampe JW, Peters U, Vaughan TL, and White E. Long-chain
omega-3 polyunsaturated fatty acid intake and risk of colorectal cancer.
Nutr Cancer 66, 716–727, 2013.
71. Brasky TM, Lampe JW, Potter JD, Patterson RE, and White E: Specialty
supplements and breast cancer risk in the VITamins And Lifestyle (VITAL)
Cohort. Cancer Epidemiol Biomarkers Prev 19, 1696–1708, 2010.
72. Brasky TM, Kristal AR, Navarro SL, Lampe JW, Peters U, et al.: Spe-
cialty supplements and prostate cancer risk in the VITamins and Lifestyle
(VITAL) cohort. Nutr Cancer 63, 573–582, 2011.
73. Torfadottir JE, Valdimarsdottir UA, Mucci LA, Kasperzyk JL, Fall K, Tet
al.: Consumption of ﬁsh products across the lifespan and prostate cancer
risk. PLoS ONE 8, e59799, 2013.
74. Szymanski KM, Wheeler DC, and Mucci LA: Fish consumption and pros-
tate cancer risk: a review and meta-analysis. Am J Clin Nutr 92,
75. Arem H, Neuhouser ML, Irwin ML, Cartmel B, Lu L, et al.: Omega-3 and
omega-6 fatty acid intakes and endometrial cancer risk in a population-
based case-control study. Eur J Nutr 52, 1251–1260, 2013.
76. Bell GA, Kantor ED, Lampe JW, Kristal AR, Heckbert SR, et al.: Intake
of long-chain omega-3 fatty acids from diet and supplements in relation
to mortality. Am J Epidemiol 179, 710–720, 2014.
77. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, et al.: The VITa-
min D and OmegA-3 TriaL (VITAL): rationale and design of a large ran-
domized controlled trial of vitamin D and marine omega-3 fatty acid
supplements for the primary prevention of cancer and cardiovascular dis-
ease. Contemp Clin Trials 33, 159–171, 2012.
6J. J. DINICOLANTONIO ET AL.
Downloaded by [18.104.22.168] at 08:53 04 November 2014