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Nutrition and Cancer
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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 Adenocarcinomas
James J. DiNicolantonioa, Mark F. McCartyb, Subhankar Chatterjeec, Carl J. Lavied & James
H. O’Keefee
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
Adenocarcinomas
James J. DiNicolantonio
Mid America Heart Institute at Saint Luke’s Hospital, Kansas City, Missouri, USA
Mark F. McCarty
Catalytic Longevity, Carlsbad, California, USA
Subhankar Chatterjee
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: jjdinicol@gmail.com
1
Nutrition and Cancer, 0(0), 1–6
Copyright Ó2014, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
DOI: 10.1080/01635581.2014.956262
Downloaded by [74.39.145.132] at 08:53 04 November 2014
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
doses.
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.
(32,33)
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
spread.
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
proposition.
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
(49).
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
TABLE 1
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
cox-2 (40)
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
Table 2.
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%
CI: 0.26–0.87).
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:
0.71–0.88 (75).
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
TABLE 2
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
nitrosamines (50,51)
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)
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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).
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