Oméga-3:
faits - thérapeutique et posologie
Formation
de tumeurs: 1,8g/jour DHA et EPA pour les cancers de l'œsophage
Les journaux spécialisés ont consacré
aux oméga-3 les articles suivants. La liste de ces publications
a été établie en avril 2003 et n'aspire nullement
à l'exhaustivité. Source: MEDLINE.
Ces données servent de référence pour les
médecins et les thérapeutes, de sorte à déterminer
la dose thérapeutique dans le cadre de la formation
de tumeurs.
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Effects
of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase
on the lipid profile and growth of human breast cancer cells.
Ge Y: Department of Medicine, Massachusetts
General Hospital and Harvard Medical School, Boston MA, USA; Chen Z,
Kang ZB, Cluette-Brown J, Laposata M, Kang JX
Anticancer Res 2002 Mar-Apr 22:537-43
Abstract
BACKGROUND: Current evidence from both experimental and human
studies indicates that omega-6 polyunsaturated fatty acids (n-6
PUFAs) promote breast tumor development, whereas long-chain n-3
polyunsaturated fatty acids (n-3 PUFAs) exert suppressive effects.
The ratio of n-6 to n-3 fatty acids appears to be an important factor
in controlling tumor development. Human cells usually have a very
high n-6/n-3 fatty acid ratio because they cannot convert n-6 PUFAs
to n-3 PUFAs due to lack of an n-3 desaturase found in C. elegans.
MATERIALS AND METHODS: Adenoviral strategies were used to introduce
the C. elegans fat-1 gene encoding an n-3 fatty acid desaturase
into human breast cancer cells followed by examination of the n-6/n-3
fatty acid ratio and growth of the cells. RESULTS: Infection of
MCF-7 cells with an adenovirus carrying the fat-1 gene resulted
in a high expression of the n-3 fatty acid desaturase. Lipid analysis
indicated a remarkable increase in the levels of n-3 PUFAs accompanied
with a large decrease in the contents of n-6 PUFAs, leading to a
change of the n-6/n-3 ratio from 12.0 to 0.8. Accordingly, production
of the eicosanoids derived from n-6 PUFA was reduced significantly
in cells expressing the fat-1 gene. Importantly, the gene transfer
induced mass cell death and inhibited cell proliferation. CONCLUSION:
The gene transfer of the n-3 fatty acid desaturase, as a novel
approach, can effectively modify the n-6/n-3 fatty acid ratio of
human tumor cells and provide an anticancer effect, without the
need of exogenous n-3 PUFA supplementation. These data also increase
the understanding of the effects of n-3 fatty acids and the n-6/n-3
ratio on cancer prevention and treatment. |
n-3
versus n-6 polyunsaturated fatty acids in critical illness.
Tashiro T: Department of Surgery, Chiba
University School of Medicine, Japan; Yamamori H, Takagi K,
Hayashi N, Furukawa K, Nakajima N
Nutrition 1998 Jun 14:551-3
Abstract
The effects of n-6 and n-3 polyunsaturated fatty acids (PUFA)
on protein metabolism, cell-mediated immunity, and production of
cytokines and prostanoids were studied in experimental animals and
patients with esophageal cancer.
In the experimental study using a rat burn model, n-6 PUFA increased
serum interleukin-6 (IL-6) and tumor necrosis factor (TNF), alpha
(P < 0.05), and decreased nitrogen balance (NB) (P < 0.05),
when compared with a fat-free control. But addition of n-3 PUFA
reduced TNF-alpha and IL-10 (P < 0.05) and improved NB (P <
0.05). Suppressed delayed type hypersensitivity (DTH) induced by
burn injury, which was not influenced by n-6 PUFA, was significantly
improved by the administration of n-3 PUFA.
n-6 PUFA tended to increase, and n-3 PUFA significantly decreased
the endotoxin translocation.
DTH, granulocyte-macrophage colony-stimulating factor, and eicosapentaenoic
acid (EPA) content increased proportionately with the intravenous
dose of fish oil emulsion. The effects of n-6 and n-3 PUFA were
studied in the patients who underwent surgery for esophageal cancer.
In the group of patients fed by total parenteral nutrition with
soybean oil emulsion, the serum IL-6 significantly increased at
2 and 6 h after operation (P < 0.05). Oral/enteral
supplementation of EPA ethyl ester (1.8 g/d) significantly reduced
the postoperative IL-6 production (P < 0.05 at 1, 2, and 6 h
after operation), and improved cell-mediated immune function 3 wk
after operation (P = 0.05). During
the chemoradiation therapy, cell-mediated immune function was improved
significantly in the patients fed enterally with EPA ethyl ester
(n = 5), when compared with the patients without EPA (n = 14).
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Influence
of n-3 fatty acids on the growth of human breast cancer cells in
vitro: relationship to peroxides and vitamin-E.
Chajès V: Institute of Medical Biochemistry, University of
Graz, Austria; Sattler W, Stranzl A, Kostner GM
Breast Cancer Res Treat 1995 Jun 34:199-212
Abstract
Epidemiological studies suggest a causal relationship of
dietary polyunsaturated fatty acids (PUFA's) with the morbidity
and mortality from breast cancer. In order to reveal possible underlying
mechanisms of these findings, we studied the influence of n-3 and
n-6 PUFA's in comparison to oleic acid on the proliferation of well
characterized estrogen dependent (MCF-7,
ZR-75, T-47-D) and estrogen independent (MDA-MB-231, HBL-100) breast
cancer cells in culture. The cell growth inhibitory effect
was related to the formation of lipid peroxidation products. Normal
human skin fibroblasts served as a control. In fibroblasts, the
addition of 20 micrograms/ml of exogenous fatty acids either had
no effect or caused an insignificant increase of proliferation.
Similar results were obtained with MCF-7 cells. In
all other breast cancer cell types, n-3 long-chain PUFA's, eicosapentaenoic
and docosahexaenoic acids, were the most effective fatty acids in
arresting the cell growth. Alpha-linolenic and gamma-linolenic
acid exerted a variable effect on cell proliferation depending on
the cell line investigated. Oleic acid significantly stimulated
the proliferation of hormone-independent breast cancer cells while
it had no effect on the proliferation of hormone-dependent cells.
Viability studies by trypan blue excretion indicated that the arrest
in cell growth was not due to major cytotoxic effects. The
addition of PUFA's to breast cancer cells caused a significant increase
in the formation of conjugated dienes and lipid hydroperoxides in
the cellular lipids; their content was significantly correlated
with the capacity of arresting cell growth. In contrast,
the addition of PUFA's to fibroblasts did not increase lipid hydroperoxide
formation. The addition of Vitamin E to cancer cells at a concentration
of 10 microM to the PUFA-supplemented medium almost completely restored
cell growth. Our data indicate that PUFA's
significantly interfere with cell proliferation of breast cancer
cells in vitro due to the formation of oxidation products.
In addition to that, there must be other factors involved, most
probably related to the differential metabolism of PUFA's in tumor
cells. Our findings may have some impact on treatment and prevention
of breast cancer. |
Immunologic
effects of national cholesterol education panel step-2 diets with
and without fish-derived N-3 fatty acid enrichment.
Meydani SN: United States Department
of Agriculture-Human Nutrition Research Center on Aging, Tufts University,
Boston MA, USA; Lichtenstein AH, Cornwall S, Meydani M,
Goldin BR, Rasmussen H, Dinarello CA, Schaefer EJ
J Clin Invest 1993 Jul 92:105-13
Abstract
Reductions in dietary fat, saturated fat, and cholesterol
have been recommended to reduce the risk of heart disease in our
society. The effects of these modifications on human cytokine production
and immune responses have not been well studied. 22
subjects > 40 yr of age were fed a diet approximating
that of the current American (14.1% of calories as saturated fatty
acids, [SFA], 14.5% monounsaturated fatty acids [MUFA], 6.1% [n-6]
polyunsaturated fatty acids [PUFA], 0.8% [n-3] PUFA, and 147 mg
cholesterol/1,000 calories) for 6 wk, after which time they consumed
(11 in each group) one of the two low-fat, low-cholesterol, high-PUFA
diets based on National Cholesterol Education Panel (NCEP) Step
2 recommendations (4.0-4.5% SFA, 10.8-11.6% MUFA, 10.3-10.5% PUFA,
45-61 mg cholesterol/1,000 calories) for
24 wk. One of the NCEP Step 2 diets was enriched in fish-derived
(n-3) PUFA (low-fat, high-fish: 0.54% or 1.23 g/d eicosapentaenoic
acid [EPA] and docosahexaenoic acid [DHA] [121-188 g fish/d])
and the other low in fish-derived (n-3) PUFA (low-fat, low-fish
[0.13% or 0.27 g/d EPA and DHA] [33 g fish/d]). Measurements of
in vivo and in vitro indexes of immune responses were taken after
each dietary period. Long-term feeding of low-fat, low-fish diet
enriched in plant-derived PUFA increased blood mononuclear cell
mitogenic response to the T cell mitogen Con A, IL-1 beta, and TNF
production and had no effect on delayed-type hypersensitivity skin
response, IL-6, GM-CSF, or PGE2 production. In contrast, the low-fat,
high-fish diet significantly decreased the
percentage of helper T cells whereas the percentage of suppressor
T cells increased. Mitogenic responses to Con A and delayed-type
hypersensitivity skin response as well as the production of cytokines
IL-1 beta, TNF, and IL-6 by mononuclear cells were significantly
reduced after the consumption of the low-fat, high-fish diet (24,
40, 45, 35, and 34%, respectively; P < 0.05 by two-tailed Student's
t test except for IL-1 beta and TNF, which is by one-tailed t test).
Our data are consistent with the concept that the
NCEP Step 2 diet that is high in fish significantly decreases various
parameters of the immune response in contrast to this diet when
it is low in fish. Such alterations may be beneficial for the prevention
and treatment of atherosclerotic and inflammatory diseases
but may be detrimental with regard to host defense against invading
pathogens. |
Docosahexaenoic
acid regulated genes and transcription factors inducing apoptosis
in human colon cancer cells.
Narayanan BA: Microarray Systems Laboratory,
Molecular Pathology and Bioinformatics Facility, American Health
Foundation, Valhalla NY, USA; Narayanan NK, Reddy BS
Int J Oncol 2001 Dec 19:1255-62
Abstract
Epidemiological and preclinical studies demonstrate that
consumption of diets high in omega-3 fatty acids (n-3 PUFAs) reduce
the risk of colon cancer. Docosahexaenoic acid (DHA), a long chain
polyunsaturated fatty acid (PUFAs) is a major constituent of nutrients
rich in n-3 PUFAs. There are studies to indicate that colon tumor
inhibition by n-3 PUFA-rich diets is, in part, mediated through
modulation of signaling pathways that alter gene expression which
are involved in colon tumor growth. In
the present study using CaCo-2 colon cancer cell lines we examined
the effects of DHA on the genetic precursors of human colon cancer
at the transcription level using DNA oligonucleotide arrays.
Our results indicated that DHA inhibits the
growth of CaCo-2 cells and induces apoptosis. For gene
expression analysis using DNA microarrays, total RNA extracted from
DHA treated CaCo-2 cells was converted to cDNA, labeled with Cy5-dCTP
(DHA-treated) and Cy3-dCTP (untreated cells) and used as probes
for hybridization in human chip spotted with 3,800 oligonucleotides
consisting of 156 functional categories. The expression profiles
of genes indicated a reprogramming pattern of previously known and
unknown genes and transcription factors that provided clues to the
possible functional mechanism of DHA. An average of (ratios from
triplicate experiments) 504 out of 3,800 genes expressed after 48
h of DHA treatment. Altered expression on the transcription factors
includes down regulation of nine members of the RNA II polymerases,
transcription co-repressor associated protein and enhancer binding
proteins such as AP2, in addition to changes in the expression of
zinc finger group of transcription factors. Activation of cytochrome
c which triggers caspases was associated with the elevated expression
of pro-apoptotic caspases 10, 13, 8, 5 and 9 in DHA treated cells.
Activation of cyclin-dependent kinase inhibitors such as p21 (waf1/cip1),
p27, p57, p19 and growth arrest specific proteins by more than 2-fold
is consistent with the induction of apoptosis and inactivation of
antiapototic Bcl-2 family of genes. Inactivation of prostaglandin
family of genes, lipoxygenases and altered expression of peroxisome
proliferators (PPARalpha and gamma) by DHA seem to indicate a lipid
peroxidation-induced apoptosis in addition to effect reflected on
the modification of cell cycle regulatory genes. These findings
support the conclusion that a genomewide expression profiling of
human colon cancer precursor genes and transcription factors provides
a set of novel regulatory mechanism(s) to determine the chemopreventive
efficacy of DHA and thus to prevent the inflammation and neoplasia.
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n-3
PUFA and alpha-tocopherol control of tumor cell proliferation.
Bartoli GM: Department of Biology, Tor
Vergata University, Rome, Italy; Palozza P, Marra G, Armelao F,
Franceschelli P, Luberto C, Sgarlata E, Piccioni E,
Anti M
Mol Aspects Med 1993 14:247-52
Abstract
Subjects at high risk for colon cancer received different
doses of fish oil on a 30-day randomized double-blind trial
to evaluate the chemopreventive effect of n-3 fatty acids against
colorectal cancer. Using rectal mucosal proliferation, assessed
with 3H-thymidine autoradiography, fish oil induced in the treated
groups but not in the placebo group a change in the proliferative
pattern, which resulted similar to that observed in low risk population;
in the same groups rectal mucosal n-3 fatty acid content increased,
where arachidonic acid level decreased. Moreover, n-3 PUFA treatment
induced modifications of Vitamin E status. The results suggest
that n-3 PUFA could protect high-risk subjects from colon cancer
by a mechanism involving a modulation of Vitamin E. |
Increased
cytotoxicity of polyunsaturated fatty acids on human tumoral B and
T-cell lines compared with normal lymphocytes.
Anel A: Departamento de Bioquímica y Biología Molecular,
Facultad de Ciencias, Universidad de Zaragoza, Spain; Naval J, Desportes
P, González B, Uriel J, Piñeiro A
Leukemia 1992 Jul 6:680-8
Abstract
Epidemiological and experimental data suggest that fatty
acids may modulate the growth of tumor cells. We have analyzed the
effect of different types of fatty acids, bound to serum proteins
in physiological conditions, on the lipid composition and growth
of human neoplastic B and T-cell lines and compared their effect
on normal lymphocyte proliferation. Fatty acids with 0 to 2 unsaturations
(stearic, oleic, and linoleic), at concentrations up to 50 or 100
microM did not significantly affect the proliferation of leukemic
cells. However, long-chain polyunsaturated fatty acids (PUFA),
and mainly docosahexaenoic (22:6, n-3), were cytotoxic at concentrations
greater than or equal to 20 microM after 48-72 h in culture. Simultaneous
supplementation with vitamin E restored normal cell growth.
The amount of end-products of lipid peroxidation in cells correlated
with the observed toxicity but the amount of superoxides did not.
Fatty acid supplementations increased cell triacylglycerol content
but did not affect the degree of unsaturation of phospholipids,
cholesterol/phospholipids molar ratio, or membrane fluidity. Glutathione-S-transferase
activity was low in Raji and CEM cells, moderate in lymphocytes
and high in Ramos cells and did not increase with supplementations.
The proliferation of normal lymphocytes, which produced lower amounts
of end-products of lipid perodixation, was not inhibited, but in
some cases stimulated, by PUFA (with the exception of 30 microM
22:6). The extension of these results to situations in vivo could
lead to use of PUFA for delaying leukemia progression or in adjuvant
chemotherapy. |
Docosahexaenoic
and eicosapentaenoic acids inhibit in vitro human endothelial cell
production of interleukin-6.
Khalfoun B: Groupe Interactions Hote-Greffon
Laboratoire D'Immunologie, Faculte De Medicine, Tours, France; Thibault F,
Watier H, Bardos P, Lebranchu Y
Adv Exp Med Biol 1997 400B:589-97
Abstract
The interaction between lymphocytes, cytokines, and endothelial
cells (EC) is a key step in the inflammatory process. Interleukin-6
(IL-6) a pleiotropic cytokine in its effects, seems to be an early
indicator of acute systemic inflammation. In this study, we have
examined the effects of polyunsaturated fatty acids (PUFAs) on the
production of IL-6 by human unstimulated EC or EC stimulated with
TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic
peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants
of immunoreactive IL-6 were measured by Sandwich ELISA. We have
shown that the production of IL-6 was potentiated when EC were stimulated
with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison
to unstimulated EC. The addition of n-3 PUFAs in culture medium
(100 ug/ml DHA or EPA) significantly reduces the production of IL-6
by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS
or depleted PBL respectively for DHA and EPA, whereas the n-6
PUFAs (Arachidonic acid), even used at the highest concentration,
was ineffective. This inhibitory effect is PUFA dose dependent
but is more potent with EPA than DHA. Regardless of the mode
of action, since IL-6 is known to be involved in hematopoiesis,
in the regulation of the immune response and in the inflammatory
reaction, these results suggest that n-3 PUFAs may play a role
in suppressing inflammation. Further studies are needed to elucidate
the mechanism involved and the choice between the two fatty acids
for clinical and therapeutic purposes. |
Linkage
between retinoid and fatty acid receptors: implications for breast
cancer prevention.
Stoll BA: Oncology Department, St Thomas'
Hospital, London SE1 7EH, UK
Eur J Cancer Prev 2002 Aug 11:319-25
Abstract
Certain dietary retinoids and polyunsaturated fatty acids
(PUFAs) consistently inhibit progression of mammary carcinogenesis
both in animal studies and cell culture, but clinically, their effect
is inconsistent. New evidence of synergistic interaction between
the nuclear receptors for the two groups of nutritional agents suggests
that appropriate selective ligands from each group might be combined
in breast cancer chemoprevention studies. Peroxisome proliferator-activated
receptor (PPAR) gamma is a nuclear receptor that is activated by
PUFAs, eicosanoids and antidiabetic agents such as troglitazone.
Such activation can cause growth inhibition in human mammary cancer
cells in culture and the effect is enhanced by ligands of retinoic
acid receptor (RAR) and retinoid X receptor (RXR). In mouse
mammary tissue in organ culture, an RXR-selective ligand has been
shown to enhance the effect of troglitazone in suppressing carcinogen-induced
pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour
growth inhibition and has been shown to bind directly to nuclear
oestrogen response elements (ERE) independently of oestrogen receptor
(ER) activity. A combination of an RXR-selective retinoid with either
troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term
study in postmenopausal women after primary surgery for intraductal
breast cancer. The resulting activation of PPAR/RXR expression may
increase response to retinoid administration, especially in the
presence of obesity and insulin resistance, because of the ability
of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I)
concentrations. Serial core biopsies of breast tissue over a short
term are proposed to identify changes in phenotype, which may influence
progression to invasiveness. In addition to cytomorphological criteria,
expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor
in the nucleus should be examined. |
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