Lim K, Han C, Xu L, et al. Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through downregulation of beta-catenin/wnt signaling pathway. Abstract no. 2679. 97th AACR Annual Meeting. Washington, DC.

Omega-3 polyunsaturated fatty acids (w3-PUFAs) are known to suppress the growth of several cancer cells, although the molecular mechanisms for their anticancer actions remain to be further understood.

This study was designed to investigate the effect and mechanism of w3-PUFAs in human hepatocellular carcinoma (HCC) cells.

Treatment of human HCC cells (Hep3B, Huh-7, HepG2) with two w3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12-48 hours resulted in a dose-dependent inhibition of cell growth, whereas arachidonic acid (AA), a w6-PUFA, exhibited no significant effect. This action likely involves apoptosis, given that DHA treatment induced cleavage form of PARP in Hep3B cells.

Furthermore, DHA and EPA treatment transiently decreased the level of phospho-GSK3-beta protein (but not phospho-AKT) and progressively reduced the beta-catenin protein in Hep3B cells.

Accordingly, DHA treatment also decreased the beta-catenin-mediated TCF-LEF reporter activity and inhibited the expression of c-Met, a beta-catenin-controlled downstream gene.

GSK3-beta inhibitors, LiCl and SB216763, partially prevented DHA-induced reduction of beta-catenin protein and TCF-LEF reporter activity and restored cell growth.

These findings suggest that w3-PUFAs inhibit HCC cell growth partly through down-regulation of phospho-GSK3-beta/beta-catenin/TCF-LEF signaling pathway.

Consequently, administration of w3-PUFA may represent a potential effective therapy for the chemoprevention and treatment of human HCC (This work was supported by NIH grants RO1 CA102325 and RO1 CA106280).

Lim K, Han C, Xu L, et al. Evidence for inhibition of beta-catenin/Wnt signaling in omega-3 polyunsaturated fatty acid-induced apoptosis of human cholangiocarcinoma cells. Abstract no. 2680. 97th AACR Annual Meeting. Washington, DC.

Cholangiocarcinoma is the second most common primary hepatobiliary malignancy in adult.

It has a high mortality rate and currently there is no effective treatment. Given its limited patient survival, a new molecular target is needed for effective chemoprevention and treatment.

Omega-3 polyunsaturated fatty acids (w3-PUFAs) are known to suppress the growth of several cancer cells, although the molecular mechanisms for their anticancer actions are not fully understood.

This study was designed to investigate the potential effect of w3-PUFAs and their mechanism of actions in human cholangiocarcinoma cells.

Treatment of human cholangiocarcinoma cells (CCLP1, HuCCT1, SG231) with two w3-PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), for 12-48 hours resulted in a dose-dependent inhibition of cell growth; in contrast, arachidonic acid (AA), a w6-PUFA, had no significant effect.

The observation that DHA induced cleavage form of PARP in CCLP1 cells indicates induction of apoptosis. Furthermore, DHA and EPA treatment transiently decreased the level of phospho-GSK3-beta (but not phospho-AKT) and progressively reduced the level of beta-catenin protein in CCLP1 cells.

DHA treatment also decreased the beta-catenin-mediated TCF-LEF reporter activity and inhibited the expression of c-Met, a bet-catenin-controlled downstream gene. GSK3-beta inhibitors, LiCl and SB216763, partially prevented DHA-induced reduction of beta-catenin protein and TCF-LEF reporter activity, and restored cell growth.

These findings suggest that w3-PUFAs inhibit cholangiocarcinoma cell growth in part through downregulation of phospho-GSK3-beta/beta-catenin/TCF-LEF signaling pathway.

Therefore, utilization of w3-PUFAs may represent a potential effective therapy for the chemoprevention and treatment of human cholangiocarcinoma (This work was supported by NIH grants RO1 CA102325 and RO1 CA106280).

Chang ET, Bälter KM, Torrång1 A, et al. Nutrient Intake and Risk of Non-Hodgkin's Lymphoma. Am J Epidemiology, 2006;164(12):1222-1232.

The mechanisms through which diet may influence the development of non-Hodgkin's lymphoma (NHL) are unclear but can be better understood by examining associations between nutrient consumption and NHL risk.

Between 2000 and 2002, 591 NHL cases and 460 population-based controls in Sweden completed a semiquantitative food frequency questionnaire. Unconditional logistic regression was performed to estimate odds ratios and 95% confidence intervals for associations with nutrient intake; all statistical tests were two sided.

Dietary intake of most macronutrients was not associated with risk of NHL or its common subtypes. Consumption of omega-3 or marine fatty acids was associated with decreased risk of NHL and chronic lymphocytic lymphoma, and dietary fiber was associated with lower risk of all subtypes examined.

When the highest and the lowest quartiles of marine fat intake were compared, the odds ratio for NHL risk was 0.6 (95% confidence interval: 0.4, 0.9), ptrend = 0.03; for dietary fiber intake, the corresponding odds ratio was 0.5 (95% confidence interval: 0.3, 0.7), ptrend < 0.001. Dietary consumption of beta-carotene or alpha-tocopherol was associated with lower NHL risk, whereas intake of calcium or retinol was associated with increased NHL risk.

Nutrients that affect inflammation, vitamin D activity, oxidative DNA damage, or DNA methylation may be associated with risk of NHL.

Jiang WG, Bryce RP, et al. Regulation of tight junction permeability and occludin expression by polyunsaturated fatty acids. Biochem Biophys Res Comm, 1998;244(2):414-420

Tight junctions (TJ) are the topical most structure in epithelial and endothelial cells and play a key role in the control of permeability and prevention of tumour cell invasion of endothelium.

In this study we examined the effects of a range of polyunsaturated fatty acids on the function of TJs and the expression of occludin, a key molecule in the TJs of the human vascular endothelial cell line, ECV304.

Treatment of the endothelial cells with gamma linolenic acid, an anti-cancer PUFA, increased the transendothelial cell resistance (TER) and reduced the paracellular permeability to large molecules.

The effects were seen without any changes in the viability of the endothelial cells.

Occludin, a recently identified molecule, which plays a major role in tight junctions was up-regulated by this fatty acid as revealed by both Western blotting and immunofluorescence.

Other fatty acids were also tested. Eicosapentaenoic acid (EPA) also exerted an up-regulatory effect, but LA and AA down-regulated the expression.

We conclude that GLA and EPA which also have other anti-cancer effects, regulate the expression of occludin in endothelial cells and thus contribute to the modification of the TER of these cells.

Brown MD, Hart CA, Gazi E, et al. Promotion of prostatic metastatic migration towards human bone marrow stoma by Omega 6 and its inhibition by Omega 3 PUFAs. Br J Cancer, 2006;94(6):842-853.

Epidemiological studies have shown not only a relationship between the intake of dietary lipids and an increased risk of developing metastatic prostate cancer, but also the type of lipid intake that influences the risk of metastatic prostate cancer.

The Omega-6 poly-unsaturated fatty acid, Arachidonic acid, has been shown to enhance the proliferation of malignant prostate epithelial cells and increase the risk of advanced prostate cancer. owever, its role in potentiating the migration of cancer cells is unknown.

Here we show that arachidonic acid at concentrations 5 M is a potent stimulator of malignant epithelial cellular invasion, which is able to restore invasion toward hydrocortisone-deprived adipocyte-free human bone marrow stroma completely.

This observed invasion is mediated by the arachidonic acid metabolite prostaglandin E2 and is inhibited by the Omega-3 poly-unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid at a ratio of 1 : 2 Omega-3 : Omega-6, and by the COX-2 inhibitor NS-398.

These results identify a mechanism by which arachidonic acid may potentiate the risk of metastatic migration and secondary implantation in vivo, a risk which can be reduced with the uptake of Omega-3 poly-unsaturated fatty acids.

Heller AR, Rossler S, Litz RJ et al. Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med, 2006; 34(4): 972-979.

OBJECTIVE: Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome.

DESIGN: Prospective, open label, multiple-center trial.

PATIENTS AND METHODS: A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for > or =3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses.

The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome.

RESULTS: The patients enrolled in this survey were (mean +/- sd) 62.8 +/- 16.5 yrs old, with a body mass index of 25.1 +/- 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 +/- 13.6. Length of hospital stay was 29.1 +/- 18.7 days (12.5 +/- 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g.kg(-1).day(-1)), was administered for 8.7 +/- 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p < .001).

The fish oil dose.kg.day did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality).

Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g.kg(-1).day(-1). Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 g.kg(-1).day(-1) were infused as compared with doses of <0.05 g.kg(-1).day(-1). After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g.kg(-1).day(-1) and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery.

CONCLUSION: Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in different diseases. Effects and effect sizes related to fish oil doses are diagnosis dependent. In view of the lack of substantial study literature concerning diagnosis-related nutritional single-substrate intervention in the critically ill, the present data can be used in formulating hypotheses and may serve as reference doses for randomized, controlled studies, which may, for instance, confirm the value of omega-3 fatty acid in the adjunctive therapy of peritonitis and abdominal sepsis.

PMID: 16484909

Jho DH, Cole SM, Lee EM, Espat NJ. Role of Omega-3 Fatty Acid Supplementation in Inflammation and Malignancy. Integrative Ca Ther, 2004;3(2): 98-111.

Omega-3 fatty acids (FAs), which include eicosapentaenoic acid (EPA) and docosahexaenoic acid, are found in fish oils and have long been investigated as components of therapy for various disease states.

Population studies initially revealed the cardioprotective and anti-inflammatory effects of omega-3 FAs and EPA, with subsequent clinical studies supporting the therapeutic role of omega-3 FAs in cardiovascular and chronic inflammatory conditions.

Prospective randomized placebo-controlled trials have also demonstrated the utility of omega-3 FA supplementation in malignancy and cancer cachexia.

In recent years, in vitro and animal studies have elucidated some of the mechanistic explanations underlying the wide range of biological effects produced by omega-3 FAs and EPA, including their antiproliferative and anticachectic actions in malignancy.

In this review, the authors discuss the recent progress made with omega-3 FAs, focusing on the advances in mechanistic understanding and the results of clinical trials.

Menendez JA, Vellon L, et al. Effect of -Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene. J. Nat. Cancer Institute, 2005; 97 (21):1611-1615.

The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro.

We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer.
Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu?overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived).

GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines.

In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site?mutated sequence was not subject to negative regulation by GLA in Her-2/neu?overexpressing cell lines.

Concurrent treatments of Her-2/neu?overexpressing cancer cells with GLA and the anti?Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.

Hardman, WE. (n-3) Fatty Acids and Cancer Therapy. J. Nutr, 2004;134:3427S-3430S.

Supplementing the diet of tumor-bearing mice or rats with oils containing (n-3) (omega-3) or with purified (n-3) fatty acids has slowed the growth of various types of cancers, including lung, colon, mammary, and prostate.

The efficacy of cancer chemotherapy drugs such as doxorubicin, epirubicin, CPT-11, 5-fluorouracil, and tamoxifen, and of radiation therapy has been improved when the diet included (n-3) fatty acids.

Some potential mechanisms for the activity of (n-3) fatty acids against cancer include modulation of eicosanoid production and inflammation, angiogenesis, proliferation, susceptibility for apoptosis, and estrogen signaling.

In humans, (n-3) fatty acids have also been used to suppress cancer-associated cachexia and to improve the quality of life.

In one study, the response to chemotherapy therapy was better in breast cancer patients with higher levels of (n-3) fatty acids in adipose tissue [indicating past consumption of (n-3) fatty acids] than in patients with lower levels of (n-3) fatty acids.

Thus, in combination with standard treatments, supplementing the diet with (n-3) fatty acids may be a nontoxic means to improve cancer treatment outcomes and may slow or prevent recurrence of cancer.

Used alone, an (n-3) supplement may be a useful alternative therapy for patients who are not candidates for standard toxic cancer therapies.

Das UN. Essential fatty acids and acquired immunodeficiency syndrome. Med Sci Monit., 2005;11(6):RA206-211

Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) that is characterized by profound immunodeficiency, opportunistic infections and Kaposi's sarcoma.

As yet no effective therapy is available for AIDS, though retroviral drugs are able to prolong life and contain HIV proliferation to some extent.

I propose that essential fatty acids (EFAs) and their metabolites could be useful in the prevention and management of AIDS.

Linoleic acid (LA) and arachidonic acid (AA) inactivate enveloped viruses, linolenic acid-enriched macrophages are markedly tumoricidal, EFAs activate macrophages and neutrophils and induce free radical generation; and cytokines bring about some of their actions by inducing the release of EFAs; gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA) prevent genetic damage and have tumoricidal actions as well; and are relatively non-toxic when administered orally or parentarally over long periods of time.

In view of this, I suggest that further studies with regard to the role of GLA, AA, EPA and/or docosahexaenoic acid (DHA) in the pathobiology of AIDS needs to be performed.

It is also proposed that possible use of these fatty acids in the prevention and treatment of AIDS needs serious consideration.

A researcher from Norway has discovered that fatty fish could have the power to destroy cancer cells.

Researcher Hilde Heimli, from the Institute for Nutrition Research at the University of Oslo, claims that fatty acids from fish oils and fatty fish can destroy the power station - the mitochondria - in certain types of cancer cells, making the cells commit suicide. Her conclusions were reported in a thesis presented at the Institute this month.

In her thesis, Heimli examined how polyunsaturated omega-3 fatty acid is ingested by different leukaemia/lymphoma cell lines and how some types of cancer cells commit suicide in this setting, in other words programmed cell death or apoptosis.

Heimli argues that if omega-3 fatty acids are to be capable of killing cancer cells, the cells have to contain a certain enzyme that activates these certain fatty acids. Cancer cells that contain less of this enzyme do not react to fish fat.

"Polyunsaturated fatty acids from fish can also initiate a less regulated cell death called necrosis. The reason for the necrotic cell death is an increased production of reactive oxygen species in the cells. It is possible to appose this necrosis by the presence of antioxidants such as vitamin C and E," Hilde Heimli told Norwegian website Kreft.no.

Heimli claims that although her experiments are developed from cancer cell lines ? cells that originally came from leukaemia patients - she believes that there should be no reason why cancer cells of other origins should not commit suicide when exposed to fish fat.

"The experiments have been done in dishes in a laboratory setting. The polyunsaturated fatty acids that are used are eicosapentaenoic acid (EPA),which are the same type as found in fatty fish or regular fish oil capsules.

The fatty acids are added to the food given to the cancer cells in a way that is most like the body's own process," explained Heimli.

The study was supported by the Norwegian Cancer Society.

Source: http://www.nutraingredients.com/news/news.asp?id=5664

Researchers at a Sydney hospital have found that fish oil can help patients with advanced bowel cancer. Scientists at Concord Hospital say that in a trial, bowel cancer patients who took fish oil with Omega 3 fatty acids respond better to chemotherapy.

Professor Stephen Clarke says cancers produce inflammatory markers in some patients that cause problems in the ability to tolerate chemotherapy. They also cause malnutrition.

But he says the anti-inflammatory and nutritional value of the fish oil has led to a better chance of successful chemotherapy.

"We've just completed a trial using fish oil supplements in this circumstance and what we found in that trial is that we were able to get patients to maintain their weight, we were able tor reduce some of these inflammatory markers and they tolerated the chemotherapy, when we treated them with it, fairly well," he said. "So that needs to be taken onto a randomised trial now."

Professor Clarke says the findings could also apply to people suffering from a range of cancers. He says more research will now be done. "There are a range of other things that we want to look at," he said.

"We want to look at just nutrition by itself, we want to look at nutritional programs combined with exercise, we want to alter the type of nutrition, you know fish oil-type nutrition versus just standard nutritional supplements.

"This is a fairly new field so there are a whole range of trials that can be undertaken."

Source: http://au.news.yahoo.com/060309/21/y64h.html

Das UN, Madhavi N, Sravan Kumar G, et al. Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites? Prostaglandins Leukot Essent Fatty Acids,1998;58(1):39-54.

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 a cids 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