from above article:
Treatments
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To achieve a sufficient incorporation of DHA into tissue cell membrane phospholipids, an amount of 1.8 g/day of DHA was chosen on the basis of earlier studies carried out in healthy individuals and recently reviewed (Arterburn et al, 2006). DHA was provided as 0.5 g capsules of DHASCO containing DHA-enriched triglyceride oil of algal origin (44% DHA providing 0.2-g DHA). DHASCO capsules were kindly supplied by Martek Biosciences Corp. (Columbia, MD, USA). Patients received nine capsules of DHASCO daily (representing 200 mg × 9=1.800 mg DHA/day), as three capsules at each meal. DHA was administered from inclusion before initiation of chemotherapy (a 7–10-day loading period) and then for the 5 months of chemotherapy. Patients were explicitly asked to avoid any intake of anti-oxidants.
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When the researchers divided the patients according to their ability to incorporate DHA, they found that those with high DHA incorporation (above the median value of 2.5%) had significantly higher TTP and OS than patients with low DHA incorporation at 8.7 versus 3.5, and 34.0 versus 18.0 months respectively.
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The abstract:
Br J Cancer. 2009 Dec 15;101(12):1978-85. Epub 2009 Nov 17.
Improving outcome of chemotherapy of metastatic breast cancer by docosahexaenoic acid: a phase II trial.
Bougnoux P,
Hajjaji N,
Ferrasson MN,
Giraudeau B,
Couet C,
Le Floch O.
INSERM U921 Nutrition, Croissance et Cancer, Tours, France.
bougnoux@med.univ-tours.fr
BACKGROUND: Breast cancer becomes lethal when visceral metastases develop. At this stage, anti-cancer treatments aim at relieving symptoms and delaying death without resulting in additional toxicity. On the basis of their differential anti-oxidant defence level,
tumour cells can be made more sensitive to chemotherapy than non-tumour cells when membrane lipids are enriched with docosahexaenoic acid (DHA), a peroxidisable and oxidative-stress-inducing lipid of marine origin. METHODS: This open-label single-arm phase II study evaluated the safety and efficacy (response rate), as primary end points, of the
addition of 1.8 g DHA daily to an anthracycline-based chemotherapy (FEC) regimen in breast cancer patients (n = 25) with rapidly progressing visceral metastases. The secondary end points were time to progression (TTP) and overall survival (OS). RESULTS: The objective response rate was 44%. With a mean follow-up time of 31 months (range 2-96 months), the median TTP was 6 months. Median OS was 22 months and reached 34 months in the sub-population of patients (n = 12) with the highest plasma DHA incorporation. The most common grade 3 or 4 toxicity was neutropaenia (80%). CONCLUSION:
DHA during chemotherapy was devoid of adverse side effects and can improve the outcome of chemotherapy when highly incorporated. DHA has a potential to specifically chemosensitise tumours.
PMID: 19920822 [PubMed - in process]
Prog Lipid Res. 2009 Aug 26. [Epub ahead of print]
Fatty acids and breast cancer: Sensitization to treatments and prevention of metastatic re-growth.
Bougnoux P,
Hajjaji N,
Maheo K,
Couet C,
Chevalier S.
Inserm U921 "Nutrition, Growth and Cancer", Université François Rabelais de Tours, Tours, France; Henry S. Kaplan Cancer Center, CHRU de Tours, Tours, France.
Lifestyle and nutritional factors have been recognized to influence breast cancer survival, irrespective of genomic alterations that are the hallmarks of the disease. The biological and molecular mechanisms involved in the effects of dietary polyunsaturated fatty acids and breast cancer response to treatments in clinical and preclinical studies have been reviewed. Among nutrients,
rumenic acid, a naturally occurring CLA isomer and n-3 docosahexaenoic acid (DHA) a highly unsaturated fatty acid, have emerged due to their potential to increase cancer treatment efficacy without additional side effects. In this review, we analyze the literature evidence that breast cancer treatment and outcome could be improved through an adjuvant dietary supplementation. Such an original approach would involve two successive phases of breast cancer treatment: an initial sensitization of residual tumor cells to chemotherapy and to radiation therapy with dietary DHA; then a prevention of metastatic re-growth with a prolonged rumenic acid supplementation. Safety is not anticipated to be a critical issue, although it has to be assessed in the long term. Dietary supplements, used in combination to anti-cancer agents, should be provided under medical prescription. Such an original use of fatty acids in breast cancer treatment could provide the lipid field with a new avenue to impact public health.
PMID: 19715726 [PubMed - as supplied by publisher]
Ann N Y Acad Sci. 2009 Aug;1171:421-7.
Inhibitory mechanism of omega-3 fatty acids in pancreatic inflammation and apoptosis.
Park KS,
Lim JW,
Kim H.
Department of Food and Nutrition, Brain Korea 21 Project, College of Human Ecology, Yonsei University, Seoul, Korea.
Oxidative stress is regarded as a major pathogenic factor in acute pancreatitis. Inflammation and apoptosis linked to oxidative stress has been implicated in cerulein-induced pancreatitis as an experimental model of acute pancreatitis. Recently, we found that reactive oxygen species mediate inflammatory cytokine expression and apoptosis of pancreatic acinar cells stimulated with cerulein. Omega-3 fatty acids show antioxidant action in various cells and tissues. In the present study, we investigated whether omega-3 fatty acids inhibit cytokine expression in cerulein-stimulated pancreatic acinar cells and whether omega-3 fatty acids suppress apoptotic cell death in pancreatic acinar cells exposed to hydrogen peroxide. We found that
omega-3 fatty acids, such as docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA), suppressed the expression of inflammatory cytokines (IL-1beta, IL-6) and inhibited the activation of transcription factor activator protein-1 in cerulein-stimulated pancreatic acinar cells. DHA and ALA inhibited DNA fragmentation, inhibited the decrease in cell viability, and inhibited the expression of apoptotic genes (p53, Bax, apoptosis-inducing factor) induced by hydrogen peroxide in pancreatic acinar cells. In conclusion,
omega-3 fatty acids may be beneficial for preventing oxidative stress-induced pancreatic inflammation and apoptosis by inhibiting inflammatory cytokine and apoptotic gene expression of pancreatic acinar cells.
PMID: 19723085 [PubMed - indexed for MEDLINE]
Biochem Pharmacol. 2010 Feb 1;79(3):421-30. Epub 2009 Sep 8.
Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid.
Saw CL,
Huang Y,
Kong AN.
Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Inflammatory response plays an important role not only in the normal physiology but also in the pathology such as cancers.
As chronic inflammations are associated with malignancies, it is important to prevent inflammation-mediated neoplastic formation, promotion and/or progression. One possible intervention will be using cancer chemopreventive agents such as curcumin (CUR), a potent anti-inflammatory and anti-oxidative stress compound.
Polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) are potent anti-inflammatory agents by decreasing the production of inflammatory eicosanoids, cytokines, and reactive oxygen species (ROS). The present study aims at examining whether CUR with DHA or EPA would have synergistic anti-inflammatory effects in RAW 264.7 cells. Non-toxic concentrations of single and combination of the compounds were investigated at 6, 12 and 24h. The nitric oxide (NO) suppression effects were most prominent at 24h.
All the combinations of CUR and DHA or EPA with lower concentrations of CUR 5 microM and 25 microM of DHA or EPA were found to have synergistic effects in suppressing LPS-stimulated NO and endogenous NO levels. Importantly, very low doses of CUR 2.5 microM and DHA or EPA of 0.78 microM could synergistically suppress the LPS-induced prostaglandin E(2) (PGE(2)). The combinations were also found to suppress iNOS, COX-2, 5-lipoxygenase (5-LOX) and cPLA(2) but induce HO-1. Taken together, the present study clearly shows the synergistic anti-inflammatory as well as anti-oxidative stress effects of CUR and PUFA.
PMID: 19744468 [PubMed - in process]
Cancer Prev Res (Phila Pa). 2009 Aug;2(8):732-42. Epub 2009 Jul 28.
Regulation of colorectal cancer cell apoptosis by the n-3 polyunsaturated fatty acids Docosahexaenoic and Eicosapentaenoic.
Giros A,
Grzybowski M,
Sohn VR,
Pons E,
Fernandez-Morales J,
Xicola RM,
Sethi P,
Grzybowski J,
Goel A,
Boland CR,
Gassull MA,
Llor X.
Department of Medicine, University of Illinois at Chicago, 840 South Wood Street (M/C 716), Chicago, IL 60612, USA.
Several studies have suggested that the n-3 fatty acids
Docosahexaenoic (DHA) and Eicosapentaenoic (EPA) have an important protective effect on colorectal cancer, and this could be at least partly due to their proapoptotic activity. It is unclear, however, how this phenomenon is triggered and what mechanisms are implicated. Here, we show that both DHA and EPA have an important proapoptotic effect on colorectal cancer cells with different molecular phenotypes but not in noncancerous cells. Apoptosis is caspase dependent, and both intrinsic and extrinsic pathways are implicated. The dimerization of Bax and Bak, the depolarization of the mitochondrial membrane, and the subsequent release of cytochrome c and Smac/Diablo to the cytosol evidence the activation of the intrinsic pathway. The implication of the extrinsic pathway is shown by the activation of caspase-8, along with the down-regulation of FLIP. The timing of caspase-8 activation, and the oligomerization of Bid with Bax, suggest a cross-talk with the intrinsic pathway. None of the death receptors that commonly initiate the extrinsic pathway: FAS, TNF-R1, and TRAIL-R2 are found to be responsible for triggering the apoptosis cascade induced by DHA and EPA. Neither PPARgamma nor cyclooxygenase-2, two likely candidates to regulate this process, play a significant role.
Our findings suggest that the down-regulation of two key regulatory elements of the extrinsic and intrinsic pathways, FLIP and XIAP, respectively, is determinant in the induction of apoptosis by DHA and EPA. These fatty acids could potentially be useful adjuvant anticancer agents in combination with other chemotherapeutic elements.
PMID: 19638488 [PubMed - indexed for MEDLINE]
Lipids Health Dis. 2009 Aug 10;8:33.
Are all n-3 polyunsaturated fatty acids created equal?
Anderson BM,
Ma DW.
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G2W1 Canada.
banderso@uoguelph.ca
N-3 Polyunsaturated fatty acids have been shown to have potential beneficial effects for chronic diseases including cancer, insulin resistance and cardiovascular disease. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in particular have been studied extensively, whereas substantive evidence for a biological role for the precursor, alpha-linolenic acid (ALA), is lacking.
It is not enough to assume that ALA exerts effects through conversion to EPA and DHA, as the process is highly inefficient in humans. Thus, clarification of ALA's involvement in health and disease is essential, as it is the principle n-3 polyunsaturated fatty acid consumed in the North American diet and intakes of EPA and DHA are typically very low. There is evidence suggesting that ALA, EPA and DHA have specific and potentially independent effects on chronic disease. Therefore, this review will assess our current understanding of the differential effects of ALA, EPA and DHA on cancer, insulin resistance, and cardiovascular disease. Potential mechanisms of action will also be reviewed. Overall, a better understanding of the individual role for ALA, EPA and DHA is needed in order to make appropriate dietary recommendations regarding n-3 polyunsaturated fatty acid consumption.
PMID: 19664246 [PubMed - indexed for MEDLINE]
From
Wikipedia:
Cancer
DHA was found to inhibit growth of human
colon carcinoma cells
[14][15], more than other omega-3
PUFAs. The cytotoxic effect of DHA wasn't caused by increased lipid peroxidation or any other oxidative damage, but rather decrease in cell growth regulators. However, different cancer lines handle PUFAs differently and display different sensitivities towards them. Such preliminary findings point to the need for further research and are not proof that DHA does or does not provide any benefit for intended treatment, cure, or mitigation of cancer. However, in 2008, DHA was shown to increase the efficacy of chemotherapy in prostate cancer cells,
[16] and in 2009, a chemoprotective effect in a
mouse model was reported.
[17]
J Surg Res. 2009 May 15. [Epub ahead of print]
A High Omega-3 Fatty Acid Diet Mitigates Murine Pancreatic Precancer Development.
Strouch MJ,
Ding Y,
Salabat MR,
Melstrom LG,
Adrian K,
Quinn C,
Pelham C,
Rao S,
Adrian TE,
Bentrem DJ,
Grippo PJ.
Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
BACKGROUND:
Diets containing omega-3 (omega-3) fat have been associated with decreased tumor development in the colon, breast, and prostate. We assessed the effects of a diet rich in omega-3 fat on the development of pancreatic precancer in elastase (EL)-Kras transgenic mice and examined the effect of an omega-3 fatty acid on pancreatic cancer cells in vitro. MATERIALS AND METHODS: Two cohorts of EL-Kras mice were fed a high omega-3 fat diet (23% menhaden oil) for 8 and 11 mo and compared with age-matched EL-Kras mice fed standard chow (5% fat). Pancreata from all mice were scored for incidence and frequency of precancerous lesions. Immunohistochemistry was performed for proliferating cell nuclear antigen (PCNA) to assess proliferative index in lesions of mice fed either a high omega-3 or standard diet.
In vitro, the effect of the omega-3 fatty acid, docosahexaenoic acid (DHA), on two pancreatic cancer cell lines was assessed. Cancer cell proliferation was assessed with an MTT assay; cell cycle analysis was performed by flow cytometry; and apoptosis was assessed with annexin/PI staining. RESULTS: The incidence, frequency, and proliferative index of pancreatic precancer in EL-Kras mice was reduced in mice fed a high omega-3 fat diet compared with mice fed a standard chow. In vitro,
DHA treatment resulted in a concentration-dependent decrease in proliferation through both G1/G0 cell cycle arrest and induction of apoptosis. CONCLUSIONS: A high omega-3 fat diet mitigates pancreatic precancer by inhibition of cellular proliferation through induction of cell cycle arrest and apoptosis.
PMID: 19631339 [PubMed - as supplied by publisher]
Cancer Chemother Pharmacol. 2001;47(1):34-40.
Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin.
Yam D,
Peled A,
Shinitzky M.
Source
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Abstract
PURPOSE:
The anticancer activity of omega-3 polyunsaturated fatty acids (omega-3 PUFA) has been shown in a large number of studies. This study was undertaken to analyze the combined effect of omega-3 PUFA and antioxidative vitamins on the level of spontaneous metastatic dissemination. The supportive effect of this dietary combination on chemotherapy with cisplatin (CP) was determined in parallel.
METHODS:
C57BL/6J mice bearing the Lewis lung carcinoma 3LL were fed ad libitum one of three isocaloric diets containing 5% soybean oil supplemented with 40 mg/kg alpha-tocopherol acetate (SO diet), or 4% fish oil plus 1% corn oil, and basal amounts of vitamin E (FO diet) or FO diet supplemented with vitamins E and C (FO+E+C diet). These diets were tested in combination with the conventional cytotoxic agent CP in a series of regimens. Tumor growth, feed consumption, body weight, lung metastasis and lung histology were followed.
RESULTS:
Both the FO dietary groups showed significantly lower tumor development than the SO group in all examined parameters, indicating that omega-3 PUFA have anticancer activity. However, the FO diet, in comparison with the FO+E+C diet induced a significantly slower rate of tumor growth, and lower metastatic load, as reflected in lung weight. The decrease in the anticancer activity of FO by the addition of vitamins E and C suggests that in situ oxidation of omega-3 PUFA underlies their anticancer action. It is thus proposed that oxidized omega-3 PUFA accumulates in the membranes and the cytosol of tumor cells, reducing their vitality and eventually leading to their death. No signs of anorexia or cachexia were observed in either FO group, in contrast to the SO group. CP treatment with the SO diet had no apparent therapeutic effect, while with the FO diets it reduced the metastatic load. The best regimen of this combined treatment was FO diet followed by CP treatment with FO diet supplemented with vitamins E and C after resection of the primary growth. This regimen could be translated to a combined therapy for human cancer.
CONCLUSIONS:
Diets enriched with omega-3 PUFA may have beneficial anticancer effects in particular when containing only basal amounts of antioxidants such as vitamin E or C. Furthermore, the addition of drugs which promote oxidation of omega-3 PUFA, such as ferrous salts (e.g. as prescribed for the treatment of anemia), may further increase these effects. However, the supportive effect of omega-3 PUFA in chemotherapy (e.g. with CP) increases when vitamins E and C are also included.
- PMID:
- 11221959
- [PubMed - indexed for MEDLINE]
Prostaglandins Leukot Essent Fatty Acids. 1998 Jan;58(1):39-54.
Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?
Das UN,
Madhavi N,
Sravan Kumar G,
Padma M,
Sangeetha P.
Source
Division of Internal Medicine, Clinical Immunology and Biochemistry, L.V. Prasad Eye Institute, Hyderabad, India.
Abstract
Tumour cell drug resistance is a major problem in cancer chemotherapy. Essential fatty acids have been shown to be cytotoxic to a variety of tumour cells in vitro. But, the effect of these fatty acids on tumour cell drug resistance has not been well characterized. Gamma-linolenic acid (GLA) of the n-6 series and eicosapentaenoic acid (EPA) of the n-3 series potentiated the cytotoxicity of anti-cancer drugs: vincristine, cis-platinum and doxorubicin on human cervical carcinoma (HeLa) cells in vitro. Alpha-linolenic acid (ALA), GLA, EPA and docosahexaenoic acid (DHA) enhanced the uptake of vincristine by HeLa cells. In addition, DHA, EPA, GLA and DGLA were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and -resistant (KB-ChR-8-5) human cervical carcinoma cells in vitro. Pre-incubation of vincristine-resistant cells with sub-optimal doses of fatty acids enhanced the cytotoxic action of vincristine. GLA, DGLA, AA, EPA and DHA enhanced the uptake and inhibited the efflux of vincristine and thus, augmented the intracellular concentration of the anti-cancer drug(s). Fatty acid analysis of KB-3-1 and KB-ChR-8-5 cells showed that the latter contained low amounts of ALA, GLA, 22:5 n-3 and DHA in comparison to the vincristine-sensitive cells. The concentrations of GLA and DHA were increased 10-15 fold in the phospholipid, free fatty acid and ether lipid cellular lipid pools of GLA and DHA treated cells. These results coupled with the observation that various fatty acids can alter the activity of cell membrane bound enzymes such as sodium-potassium-ATPase and 5'-nucleotidase, levels of various anti-oxidants, p53 expression and the concentrations of protein kinase C suggest that essential fatty acids and their metabolites can reverse tumour cell drug-resistance at least in vitro.
- PMID:
- 9482165
- [PubMed - indexed for MEDLINE]
Br J Cancer. 1993 Apr;67(4):728-33.
Effect of polyunsaturated fatty acids on the drug sensitivity of human tumour cell lines resistant to either cisplatin or doxorubicin.
Plumb JA,
Luo W,
Kerr DJ.
Free PMC Article
Source
CRC Department of Medical Oncology, University of Glasgow, Bearsden, UK.
Abstract
Growth of cells in vitro in the presence of fatty acids can alter the membrane composition and hence fluidity and permeability. Exposure of both doxorubicin (2780AD) and cisplatin (2780CP) resistant human ovarian cell lines to non-toxic concentrations of polyunsaturated fatty acids (gamma-linolenic acid and eicosapentaenoic acid) either before or during exposure to the cytotoxic drug did not modulate drug sensitivity. However, the fatty acids were toxic in their own right. Whilst the ovarian cell lines 2780AD and 2780CP showed a small degree of cross resistance to both fatty acids the doxorubicin resistant breast cell line MCF7/Adr was slightly more sensitive than MCF7. When the interactions between the polyunsaturated fatty acids and cytotoxic drugs were analysed by the isobologram method the toxicities were shown to be additive. The combination of polyunsaturated fatty acids and cytotoxic drugs may have clinical potential provided that the normal tissue toxicities of the two treatments are not additive.
- PMID:
- 8385976
- [PubMed - indexed for MEDLINE]
- PMCID: PMC1968342
Curr Med Chem. 2011 Aug 9. [Epub ahead of print]
Differential Anti-Cancer Effects of Purified EPA and DHA and Possible Mechanisms Involved.
Serini S,
Fasano E,
Piccioni E,
Cittadini AR,
Calviello G.
Source
Institute of General Pathology, UniversitÃ* Cattolica del S. Cuore, L.go F. Vito, 1 00168 Rome, Italy.
g.calviello@rm.unicatt.it.
Abstract
As the concepts of pharmaconutrition are receiving increasing attention, it seems essential to clearly assess the effects of specific dietary compounds in specific groups of patients or clinical conditions. We are herein interested in better defining the differential anti-neoplastic effects of the two major n-3 long chain polyunsaturated fatty acids present in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The efficiency of these fatty acids represents a subject of intense interest and debate, and whereas plenty of preclinical studies have strongly demonstrated their preventive and therapeutic effect in different kinds of cancers, the results of the epidemiologic studies are still controversial, and only a few trials have been performed. It has been reported that EPA and DHA may act either through the same or different mechanisms, thus suggesting that a differential efficacy could exist. At present, however, this point has not been clarified, although its better comprehension would allow a more proper and effective use of these fatty acids in the human interventional studies. In an attempt to elucidate this aspect we have herein analyzed the data obtained in the studies which have directly compared the antitumor effects of separate treatments with EPA or DHA. Most of the in vitro data indicate DHA as the more powerful antineoplastic agent. However, an equivalent efficiency of EPA and DHA is suggested by the few in vivo studies. Possible reasons for this discrepancy are discussed and pathways of cell growth that could be differentially influenced by EPA and DHA are described.
- PMID:
- 21824086
- [PubMed - as supplied by publisher]
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