(fatty acids, omega 3 [majr]) & (neoplasms [majr]) (only with abstract)

501 articles - 08.09.10

1: Arch Surg. 2010 Jun;145(6):515-20.

Omega-3 fatty acids: investigations from cytokine regulation to pancreatic cancer gene suppression.

Boutros C, Somasundar P, Razzak A, Helton S, Espat NJ.

Department of Hepatobiliary and Surgical Oncology, Roger Williams Medical Center, 825 Chalkstone Ave, Prior 4, Providence, RI 02908, USA.

Omega-3 (omega-3) fatty acids have been clinically and experimentally associated with the amelioration of chronic and acute inflammation; however, the mechanisms for these observations have not been well defined. During the past decade, laboratories of nutrition and inflammation have demonstrated that the anti-inflammatory activities of omega-3 fatty acids occur at least in part through the inhibition of macrophage-elaborated tumor necrosis factor production and through inactivation of the nuclear factor-kappaB signaling pathway subsequently altering proinflammatory cytokine transcription. These observations led to further experiments that support a role for omega-3 fatty acids in the restoration of apoptosis in various chemoresistant tumor models through a similar inactivation of the nuclear factor-kappaB signaling pathway. The potential for nutritional modulation of host inflammation has been an ongoing and expanding area of investigation. An increased emphasis has been placed on the potential for diet and dietary supplements to serve as modulators of host response to disease, injury, and infection.

Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20566969&dopt=ExternalLink

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2: Eur Rev Med Pharmacol Sci. 2010 Apr;14(4):292-301.

Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer cachexia.

Mantovani G.

Department of Medical Oncology, Schoool of Medicine, University of Cagliari, Italy. mantovan@medicina.unica.it

BACKGROUND AND OBJECTIVE: A phase III randomised study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia: lean body mass (LBM), resting energy expenditure (REE), fatigue; and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. PATIENTS: Three hundred and thirty-two assessable patients with cancer-related anorexia/cachexia syndrome (CACS) were randomly assigned to one of five arms of treatment: 1--medroxyprogesterone 500 mg/d or megestrol acetate 320 mg/d; 2--oral supplementation with eicosapentaenoic acid (EPA); 3--L-carnitine 4 g/d; 4--thalidomide 200 mg/d; 5--a combination of the above. Treatment duration: 4 months. RESULTS: Analysis of variance showed a significant difference between the treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5. IL-6 decreased significantly in arm 5 and 4. GPS significantly decreased in arms 5, 4 and 3. Total daily physical activity showed that total energy and active energy expenditure increased significantly in arm 5. Eastern Cooperative Oncology group-Performance Status (ECOG-PS) significantly decreased in arms 5, 4 and 3. Toxicity was substantially negligible, comparable between treatment arms. CONCLUSIONS: The most effective treatment for all three primary efficacy endpoints as well as secondary endpoints appetite, IL-6, GPS and ECOG PS was the combination regimen that included all selected agents.

Publication Types: Clinical Trial, Phase III Randomized Controlled Trial

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20496538&dopt=ExternalLink

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3: Cell Cycle. 2010 May;9(9):1824-9. Epub 2010 May 15.

Dietary n-3 polyunsaturated fatty acids fail to reduce prostate tumorigenesis in the PB-ErbB-2 x Pten(+/-) preclinical mouse model.

Vissapragada S, Ghosh A, Ringer L, Salinas P, Brophy A, Peaceman D, Kallakury B, Banerjee PP, Fricke ST, Helfrich W, Lee YC, Pestell R, Scherer P, Tanowitz HB, Avantaggiati ML, Hilakivi-Clarke L, Lisanti MP, Rodriguez OC, Albanese C.

Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.

Diet and obesity, and their associated metabolic alterations, are some of the fastest-growing causes of disease and death in America. Findings from epidemiological studies correlating obesity, the sources of dietary fat and prostate cancer (PCa) are conflicting. We have previously shown that 15% of PB-ErbB-2 x pten(+/-) mice developed PCa and exhibited increased phosphorylated 4E-BP1, but not the key PI3-kinase intermediary phospho-protein, mTOR, when maintained on unrefined mouse chow. We report herein that 100% of animals fed refined, westernized AIN-93-based diets containing corn oil developed PCa by 12 months of age. Increases in visceral fat and mTO R activation in the tumors were also observed. Furthermore, nuclear cyclin E levels were significantly induced by the AIN-93-corn oil-based diets versus chow. Replacing 50% of the corn oil with menhaden oil, with 21% of its triglycerides being n-3 PUFA's, had no effect on tumorigenesis, fat deposition, cyclin E or mTOR. Phosphorylated BAD levels were similar in the tumors of mice in all three diets. Our data demonstrated that in the context of our preclinical model, components of crude chow, but not dietary n-3 PUFAs, protect against PCa progression. In addition, these data establish phosphorylated mTOR, nuclear cyclin E and visceral fat deposits as possible biomarkers of increased dietary risk for PCa.

Publication Types: Research Support, N.I.H., Extramural

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20404514&dopt=ExternalLink

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4: Am J Epidemiol. 2010 May 1;171(9):969-79. Epub 2010 Apr 14.

Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans.

Kim S, Sandler DP, Galanko J, Martin C, Sandler RS.

Epidemiology Branch, National Institute of Environmental Health Sciences, P.O. Box 12233, MD A3-05, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709, USA. kims3@niehs.nih.gov

Long-chain omega-3 polyunsaturated fatty acids (PUFAs) may have antineoplastic properties in the colon. The authors examined the association between intakes of different PUFAs and distal large bowel cancer in a population-based case-control study of 1,503 whites (716 cases; 787 controls) and 369 African Americans (213 cases; 156 controls) in North Carolina (2001-2006). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals for distal large bowel cancer risk in relation to quartiles of PUFA intake. Increased consumption of long-chain omega-3 PUFAs was associated with reduced risk of distal large bowel cancer in whites (multivariable odds ratios = 0.88 (95% confidence interval (CI): 0.63, 1.22), 0.69 (95% CI: 0.49, 0.98), and 0.49 (95% CI: 0.34, 0.71) for second, third, and highest vs. lowest quartile) (P(trend) < 0.01). Intake of individual eicosapentaenoic acids and docosahexaenoic acids was inversely related to distal large bowel cancer risk, whereas the ratio of omega-6 to long-chain omega-3 PUFAs was associated with increased risk of distal large bowel cancer in whites, but not among African Americans (P(interaction) < 0.05). Study results support the hypothesis that long-chain omega-3 PUFAs have beneficial effects in colorectal carcinogenesis. Whether or not the possible benefit of long-chain omega-3 PUFAs varies by race warrants further evaluation.

Publication Types: Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20392864&dopt=ExternalLink

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5: Prostaglandins Leukot Essent Fatty Acids. 2010 Apr-Jun;82(4-6):237-41. Epub 2010 Apr 2.

Fatty acids and breast cancer: the role of stem cells.

Erickson KL, Hubbard NE.

Department of Cell Biology and Human Anatomy, University of California, School of Medicine, Davis, CA 95616-8643, USA. klerickson@ucdavis.edu

Studies with animal models in vivo as well as with animal and human tumor cells in vitro suggest that specific fatty acids could reduce breast tumorigenesis. The most striking dietary fatty acid studies in animal models that show promise for reduction of breast cancer risk in humans are with conjugated linoleic acids (CLA) and n-3 fatty acids. Although a number of mechanisms have been proposed, the specific target of those fatty acids is not yet known. We sought to determine whether the effects of those fatty acids on terminally differentiated tumor cell seen could be due to alteration of breast cancer stem cells. The isomers, cis9, trans11-CLA and trans10, cis12-CLA, and the n-3 fatty acids, docosahexaenoic and eicosapentaenoic, reduced the proliferation of, and had increased toxicity towards, mammary tumor initiating cells. One mechanism involved in the effect of n-3 fatty acids may be due to alteration of the profile of prostaglandins. These results indicate that select fatty acids may be useful for preventing or reducing the risk of breast cancer as they may target the tumor initiating cell. Copyright 2010 Elsevier Ltd. All rights reserved.

Publication Types: Research Support, U.S. Gov't, Non-P.H.S.

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20363115&dopt=ExternalLink

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6: Nutr Cancer. 2010 Apr;62(3):284-96.

Enhancing cytotoxic therapies for breast and prostate cancers with polyunsaturated fatty acids.

Shaikh IA, Brown I, Wahle KW, Heys SD.

Cancer Medicine Group, Division of Applied Medicine, Medical School, University of Aberdeen, Aberdeen, UK.

The role of omega-3 and omega-6 fatty acids has been extensively studied in most of the human malignancies including breast, colon, prostate, pancreas, and stomach cancers. In particular, the role of omega-3 and omega-6 fatty acids in carcinogenesis has been extensively investigated in epidemiological, laboratory cell culture studies and studies in vivo in animal. Findings from these studies suggest that omega-3 and omega-6 fatty acids are cytotoxic in different cancers and act synergistically with cytotoxic drugs. Although experimental evidence for the potential beneficial role of polyunsaturated fatty acids (PUFAs) in enhancing the effectiveness of various chemotherapeutic agents in animal models and in cell culture studies is increasing, there are only a few reports that have shown supportive evidence for linking these natural compounds with augmentation of anticancer chemotherapeutics in human trials. This review presents evidence for a commonality in the proposed molecular mechanisms of action elicited by various PUFAs believed to be responsible for their enhancement of the effectiveness of anticancer chemotherapy, specifically in breast and prostate cancers, and reviews laboratory and animal studies and few reported human clinical trials. It concludes that sufficient evidence is available to suggest that major clinical trials with these natural compounds as adjuncts to standard therapies should be undertaken as a priority.

Publication Types: Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20358465&dopt=ExternalLink

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7: Gut. 2010 Jul;59(7):918-25. Epub 2010 Mar 26.

Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis.

West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA.

Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.

OBJECTIVE: The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anticolorectal cancer activity in vitro and in preclinical models. The present study tested whether a novel, enteric-coated formulation of EPA, as the free fatty acid (EPA-FFA), has chemopreventative efficacy in patients with familial adenomatous polyposis (FAP), in a randomised, double-blind, placebo-controlled trial. METHODS: Patients undergoing endoscopic surveillance of their retained rectum postcolectomy were randomised to EPA-FFA (SLA Pharma) 2 g daily or placebo for 6 months. The number and size of polyps in an area of mucosa defined by a tattoo were determined before and after intervention. Global rectal polyp burden was scored (-1, 0, +1) by examination of video endoscopy records. Mucosal fatty acid content was measured by gas chromatography-mass spectrometry. RESULTS: 55 patients with FAP were evaluated by an intention-to-treat analysis (EPA-FFA 28, placebo 27). Treatment with EPA-FFA for 6 months was associated with a mean 22.4% (95% CI 5.1% to 39.6%) reduction in polyp number (p=0.012) and a 29.8% (3.6% to 56.1%) decrease in the sum of polyp diameters (p=0.027). Global polyp burden worsened over 6 months in the placebo group (-0.34) unlike the EPA-FFA group (+0.09, difference 0.42 (0.10-0.75), p=0.011). EPA-FFA treatment led to a mean 2.6-fold increase in mucosal EPA levels (p=0.018 compared with placebo). EPA-FFA was well tolerated with an incidence of adverse events similar to placebo. CONCLUSIONS: EPA-FFA has chemopreventative efficacy in FAP, to a degree similar to that previously observed with selective cyclo-oxygenase-2 inhibitors. EPA holds promise as a colorectal cancer chemoprevention agent with a favourable safety profile.

Publication Types: Randomized Controlled Trial Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20348368&dopt=ExternalLink

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8: Am J Clin Nutr. 2010 May;91(5):1185-94. Epub 2010 Mar 24.

Omega-3 fatty acid supplements in women at high risk of breast cancer have dose-dependent effects on breast adipose tissue fatty acid composition.

Yee LD, Lester JL, Cole RM, Richardson JR, Hsu JC, Li Y, Lehman A, Belury MA, Clinton SK.

Department of Surgery, The Ohio State University, Columbus, OH, USA. lisa.yee@osumc.edu

BACKGROUND: Preclinical evidence of the preventive benefits of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) in breast cancer continues to fuel interest in the potential role of dietary fat content in reducing breast cancer risk. The dose of fish-oil/omega-3 PUFAs needed to achieve maximal target tissue effects for breast cancer prevention remains undefined. OBJECTIVE: To determine the dose effects of omega-3 fatty acids on breast adipose tissue fatty acid profiles, we conducted a study of 4 doses of omega-3 PUFAs in women at high risk of breast cancer. DESIGN: In this 6-mo randomized open-label study, 48 women with increased breast cancer risk received 1, 3, 6, or 9 capsules/d of an omega-3 PUFA supplement that provided 0.84, 2.52, 5.04, and 7.56 g docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) daily, respectively. Subjects made monthly visits, at which time pill counts were made and fasting blood samples were collected to determine fatty acid profiles; anthropometric measurements were made, breast adipose tissue samples were collected, and laboratory tests of toxicity (alanine aminotransferase, LDL cholesterol, and platelet function) were made at baseline and at 3 and 6 mo. RESULTS: All doses led to increased serum and breast adipose tissue EPA and DHA concentrations, but the response to 0.84 g DHA+EPA/d was less than the maximum possible response with > or = 2.52 g/d. Body mass index attenuated the dose response for serum tissue DHA and EPA (P = 0.015 and 0.027, respectively) and breast adipose tissue DHA (P = 0.0022) in all of the treatment groups. The incremental increase in DHA and EPA correlated inversely with baseline fat and serum values. Compliance over 6 mo was 92.9 +/- 9.2% and was unaffected by treatment arm. No severe or serious toxicities were reported. CONCLUSIONS: Daily doses up to 7.56 g DHA+EPA were well tolerated with excellent compliance in this cohort at high risk of breast cancer. Body mass index and baseline fatty acid concentrations modulated the dose-response effects of omega-3 PUFA supplements on serum EPA and DHA and breast adipose tissue DHA.

Publication Types: Randomized Controlled Trial Research Support, N.I.H., Extramural

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20335550&dopt=ExternalLink

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9: Exp Cell Res. 2010 May 1;316(8):1365-73. Epub 2010 Mar 6.

Omega-3 fatty acids in cancer, the protectors of good and the killers of evil?

Gleissman H, Johnsen JI, Kogner P.

Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, S-171 76, Stockholm, Sweden.

Omega-3 fatty acids have been implicated in cancer prevention and treatment. Conventional chemotherapeutics are considered "double-edged swords", as they kill the cancer cells but also strike the healthy cells causing severe morbidity and sometimes also mortality. Could omega-3 fatty acids in this setting work as a "sword and shield" instead, by being cytotoxic to cancer cells, but at the same time protect healthy cells from these deleterious effects? In addition, may our current diet with decreased omega-3/omega-6 ratio contribute to the increased cancer incidence, and could an omega-3 enriched diet be used as a preventive measure against cancer? Here, we seek answers to these questions by reviewing the effects of omega-3 fatty acids, particularly DHA, on various cancers with emphasis on a cancer of neural origin, neuroblastoma. Results from preventive and therapeutic animal as well as human studies together with mechanisms behind the observed toxicity are summarized. Copyright 2010. Published by Elsevier Inc.

Publication Types: Research Support, Non-U.S. Gov't Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20211172&dopt=ExternalLink

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10: Int J Oncol. 2010 Apr;36(4):991-8.

The cell cycle effects of docosahexaenoic acid on human metastatic hepatocellular carcinoma proliferation.

Lee CY, Sit WH, Fan ST, Man K, Jor IW, Wong LL, Wan ML, Tan-Un KC, Wan JM.

School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China.

Given the reported side effects associated with chemotherapy and surgical resection, dietary intervention with omega-3 polyunsaturated fatty acids (PUFAs) has been postulated to be an alterative way to prevent liver cancer progression and metastasis. We studied the effects of an omega-3 PUFA, docahexaenoic acid (DHA) on COX-2 expression and the cell cycle control machinery that co-ordinately regulate the HCC cells growth. Our data showed that DHA (0-200 microM) retarded proliferation of the human metastatic HCC cell line MHCC97L dose-dependently. In addition, inhibition of cyclin A/Cdk2 interfered with S-phase progression further in agreement with the result of bivariate flow cytometric analysis which indicated that DNA synthesis time (Ts) was significantly prolonged by DHA in MHCC97L. The N-myc oncogene, the heat shock proteins Hsp27 and glucose-related protein 78 (GRP78) as well as the antioxidant enzymes superoxide dismutase may play significant roles in the cell cycle control and reduced-proliferation of MHCC97L by DHA. Our data indicated that it is imperative to develop therapeutic strategy with omega-3 PUFA that simultaneously targets COX-2 and other cell cycle regulators in hepatocarcinogenesis. This study provides novel mechanistic insights into the modulation of DHA on human hepatocarcinoma.

Publication Types: Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20198345&dopt=ExternalLink

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11: Oncologist. 2010;15(2):200-11. Epub 2010 Feb 15.

Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia.

Mantovani G, Maccio A, Madeddu C, Serpe R, Massa E, Dessi M, Panzone F, Contu P.

Department of Medical Oncology,University of Cagliari, Cagliari, Italy. mantovan@medicina.unica.it

PURPOSE: A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. PATIENTS AND METHODS: Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. RESULTS: Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. CONCLUSION: The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents.

Publication Types: Clinical Trial, Phase III Randomized Controlled Trial

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20156909&dopt=ExternalLink

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12: Laryngorhinootologie. 2010 Feb;89(2):103-13. Epub 2010 Feb 12.

[The significance of perioperative immunonutrition]

[Article in German]

Schreiter D, Rabald S, Bercker S, Kaisers UX.

Perioperative immunonutrition is aiming at modulating altered immunological and metabolic functions in the context of major surgery. It is defined as the supplementation of constitutionally essential substrates such as glutamine, arginine, omega-3-fatty acids or nucleotides. The application of such formula is recommended for patients undergoing major abdominal-surgical procedures and tumour surgery in the head neck area. The substitution should be given 5-7 days before and after the intervention.

Publication Types: English Abstract Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20155649&dopt=ExternalLink

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13: Gynecol Oncol. 2010 May;117(2):341-7. Epub 2010 Feb 13.

Decreased severity of ovarian cancer and increased survival in hens fed a flaxseed-enriched diet for 1 year.

Ansenberger K, Richards C, Zhuge Y, Barua A, Bahr JM, Luborsky JL, Hales DB.

Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA.

OBJECTIVE: With the exception of the laying hen, no other animal model of spontaneous ovarian surface epithelial cancer replicates the human disease. Flaxseed is the richest vegetable source of omega-3 fatty acids, which are chemopreventive in breast cancer and may be important in other cancers. The objective of this study was to determine if a flaxseed-enriched diet had a chemopreventive effect on ovarian cancer in the laying hen. METHODS: White Leghorn hens were fed with 10% flaxseed-enriched or standard diet for 1 year. The incidence and severity of ovarian cancer were determined by gross pathology and histology in the two groups. General health markers were also measured. Eggs were collected and analyzed by gas chromatography to determine omega-3 fatty acid levels. RESULTS: A significant reduction in late stage ovarian tumors was detected in the flaxseed-fed hens. Incidence rates of ovarian cancer were not significantly different between the two groups. The results indicate that a flaxseed diet increases overall survival in the laying hen. Flaxseed-fed hens' eggs incorporated significantly more omega-3 fatty acids compared to control hens. CONCLUSIONS: These findings show that 10% flaxseed supplementation for 1 year in the laying hen results in a significant reduction in the severity of ovarian cancer, but no change in the incidence of the disease. Hens fed flaxseed had overall better health and reduced mortality. These findings may provide the basis for a clinical trial that evaluates the efficacy of flaxseed as a chemosuppressant of ovarian cancer in women. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20153884&dopt=ExternalLink

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14: Bioorg Med Chem. 2010 Mar 1;18(5):1866-74. Epub 2010 Jan 25.

Characterization of anticancer properties of 2,6-diisopropylphenol-docosahexaenoate and analogues in breast cancer cells.

Harvey KA, Xu Z, Whitley P, Davisson VJ, Siddiqui RA.

Cellular Biochemistry Laboratory, Methodist Research Institute, Clarian Health Partners, Inc., 1800 N. Capital Ave., Indianapolis, IN 46202, USA.

The present study describes the characterization and evaluation of novel anticancer conjugates, 2,6-diisopropylphenol-docosahexaenoate (PP-DHA), and its analogues including 2,4-diisopropylphenol-docosahexaenoate (DIPP-DHA), 2-isopropylphenol-docosahexaenoate (IPP-DHA), 2-cyclohexanephenol-docosahexaenoate (CHP-DHA) and phenol-docosahexaenoate (P-DHA) on breast cancer cell lines. Representative breast cancer cell lines, based on estrogen alpha receptor (ER) and oncogene Her-2 expression, were used and include MDA-MB-231 (ER-negative, Her-2-negative), MCF-7 (ER-positive, Her-2-negative) AU565 (ER-negative, Her-2-positive) and MDA-MB-361 (ER-positive, Her-2-positive). The PP-DHA conjugate significantly inhibited cell growth and induced cell loss in the breast cancer cell lines similarly; however, this conjugate was not effective against normal mammary epithelial cells. The effect of various conjugates were in PP-DHA>IPP-DHA>DIPP-DHA>CHP-DHA>>P-DHA order. PP-DHA and IPP-DHA conjugates were stable in human and mouse serum. Furthermore, the non-hydrolyzable amide-linked conjugate analogues affected breast cancer cells in a manner similar to that of the ester-linked conjugates. This suggests that ester-linked PP-DHA and IPP-DHA conjugates were stable during treatment to breast cancer cells due to structural hindrance. PP-DHA did not affect PPARalpha or PPARgamma activities but its anticancer effects appear to be mediated in part though the inhibition of histone deacetylase (HDAC) activity. Further experiments are needed to confirm their molecular target and to test the effectiveness of these compounds in an in vivo model for their anticancer properties. In conclusion, these results suggest that the novel PP-DHA and IPP-DHA conjugates and their amide derivatives may be useful for the treatment of breast cancer. Copyright 2010 Elsevier Ltd. All rights reserved.

Publication Types: Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20153203&dopt=ExternalLink

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15: Apoptosis. 2010 May;15(5):621-30.

Fish fatty acids alter markers of apoptosis in colorectal adenoma and adenocarcinoma cell lines but fish consumption has no impact on apoptosis-induction ex vivo.

Habermann N, Schon A, Lund EK, Glei M.

Department of Nutritional Toxicology, Institute for Nutrition, Friedrich-Schiller-University Jena, Jena, Germany. nina.habermann@gmail.com

Previous studies suggest that the n-3 polyunsaturated fatty acids (PUFAs) eicosapenteinoic acid (EPA) and docosahexaenoic acid (DHA), constituents of fish oil, exert chemopreventive activity in colon cancer. One of the mechanisms involved is the facilitation of apoptosis. While a pro-apoptotic potential of n-3 PUFAs has been suggested, it is still unclear whether additional consumption of fish will also lead to comparable results. The aim of this study was to assess EPA- and DHA-mediated effects on endpoints of apoptosis and to use a novel biomarker-approach to measure modulation of apoptosis by consumption of fish. LT97 human colon adenoma and HT29 human colon adenocarcinoma cells were used to investigate modulation of apoptosis by EPA, DHA or linoleic acid (LA) using a set of endpoints, namely phosphatidylserine staining with Annexin-V (flow cytometry), Bcl-2 expression (Real-time RT-PCR), and Bid, caspase 3, 8 and 9 expression as well as PARP cleavage (Western Blot). Furthermore, faecal water (FW) of volunteers (n = 89) from a human trial intervening with fish was used to investigate changes in apoptosis by flow cytometry. DHA was more effective at inducing apoptosis than EPA. LT97 cells were more prone to DHA and EPA induced apoptosis than HT29 cells. Treatment of LT97 cells with FW from volunteers consuming fish did not result in any changes in apoptosis. Taken together, our results show that adenoma cells are highly susceptible to n-3 PUFA-induced apoptosis. By using a biomarker-approach (FW) to measure apoptosis-induction ex vivo no change in apoptosis after additional fish consumption was detectable.

Publication Types: Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20107900&dopt=ExternalLink

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16: Oncol Res. 2009;18(2-3):83-94.

Omega-3 and omega-6 polyunsaturated fatty acids enhance arsenic trioxide efficacy in arsenic trioxide-resistant leukemic and solid tumor cells.

Wirtitsch M, Roth E, Bachleitner-Hofmann T, Wessner B, Sturlan S.

Surgical Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Recently we showed that the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) sensitizes arsenic trioxide (As2O3)-resistant tumor cells to a clinically achievable concentration (1 microM) of As2O3 via a reactive oxygen species (ROS)-dependent mechanism. The aim of the present study was to evaluate, whether this combined effect of As2O3 and DHA is also applicable to other PUFAs [i.e., eicospentaenoic acid (EPA), arachidonic acid (AA), and gamma-linolenic acid (GLA)]. Fourteen tumor cell lines were incubated with As2O3 (1 microM), PUFA (25-100 microM), or the combination thereof (+/- vitamin E). Cell viability (colorimetric), apoptosis (bivariate annexin V/propidium iodide staining, detection of hypodiploid DNA), and thiobarbituric acid reactive substances (TBARS) were evaluated. Twelve of 14 As2O3-resistant cell lines tested were resistant to PUFA monotherapy. However, combined treatment with As2O3 and either PUFA significantly reduced cell viability in a dose-dependent manner with AA being the most potent As2O3 enhancer. The combined cytotoxic effect of As2O3/AA treatment was due to induction of apoptosis, preceded by increased intracellular TBARS and was abolished by the antioxidant vitamin E. Importantly, the combined effect of As2O3 and AA was selectively toxic for malignant cells because no cytotoxic effect was observed in normal skin fibroblasts and human microvascular endothelial cells. In conclusion, our study shows that also other PUFAs than DHA-and in particular the omega-6-PUFA AA--can be used as effective modulators of tumor cell chemosensitivity to clinically achievable concentrations of As2O3. Enhanced lipid peroxidation most likely constitutes the key mechanism for the combined effect.

Publication Types: Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20066898&dopt=ExternalLink

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17: Lipids Health Dis. 2009 Dec 15;8:54.

Cytotoxicity of unsaturated fatty acids in fresh human tumor explants: concentration thresholds and implications for clinical efficacy.

Scheim DE.

dscheim@nei.nih.gov

BACKGROUND: Unsaturated fatty acids (UFAs) exhibit in vitro cytotoxicity against many malignant cell lines and yield decreased cancer incidence and reduced tumor growth in animal models. But clinical and animal studies to date have achieved response using only localized delivery methods such as intratumoral infusion. To explore possibilities for enhanced clinical efficacy, fresh surgical explants of tumors from 22 patients with five malignancies were exposed to gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) and analyzed with an in vitro chemosensitivity testing system, the Fluorescent Cytoprint Assay (FCA). A total of 282 micro-organ cultures derived from these malignant tumors were exposed to GLA and ALA at different concentrations. RESULTS: GLA and ALA exhibited greater than 90% cytotoxicity at a sharp concentration threshold between 500 microM and 1 mM against all but two malignant micro-organ cultures tested in 5-10% serum. In tests using 30-40% serum, GLA and ALA killed tumor at concentrations of 2 mM and above. CONCLUSIONS: The concentration threshold of 500 microM to 2 mM exhibited for antitumor activity by GLA and ALA is much higher than that observed in most previously reported cell culture studies but consistent with physiological concentrations found to kill tumor clinically and in animals. A mechanism of antitumor activity by unsaturated fatty acids through selective destabilization of the malignant plasma membrane is considered. An oral regimen is proposed for phase I clinical testing that could push the area under the curve for serum concentration of unbound unsaturated fatty acids over time to much higher levels than previously achieved for systemic administration and into the range that could yield antitumor response.

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=20003514&dopt=ExternalLink

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18: Carcinogenesis. 2010 Mar;31(3):489-95. Epub 2009 Dec 7.

Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells.

Dimri M, Bommi PV, Sahasrabuddhe AA, Khandekar JD, Dimri GP.

Department of Medicine, NorthShore University HealthSystem Research Institute, 1001 University Place, Evanston, IL 60201, USA.

The polycomb group (PcG) protein, enhancer of zeste homologue 2 (EZH2), is overexpressed in several human malignancies including breast cancer. Aberrant expression of EZH2 has been associated with metastasis and poor prognosis in cancer patients. Despite the clear role of EZH2 in oncogenesis and therapy failure, not much is known about chemotherapeutics and chemopreventive agents that can suppress its expression and activity. Here, we show that dietary omega-3 (omega-3) polyunsaturated fatty acids (PUFAs) can regulate the expression of EZH2 in breast cancer cells. The treatment of breast cancer cells with omega-3 PUFAs, but not omega-6 PUFAs, led to downregulation of EZH2. Studies using proteosome inhibitor MG132 suggested that omega-3 PUFAs induce degradation of the PcG protein EZH2 through posttranslational mechanisms. Furthermore, downregulation of EZH2 by omega-3 PUFAs was accompanied by a decrease in histone 3 lysine 27 trimethylation (H3K27me3) activity of EZH2 and upregulation of E-cadherin and insulin-like growth factor binding protein 3, which are known targets of EZH2. Treatment with omega-3 PUFAs also led to decrease in invasion of breast cancer cells, an oncogenic phenotype that is known to be associated with EZH2. Thus, our studies suggest that the PcG protein EZH2 is an important target of omega-3 PUFAs and that downregulation of EZH2 may be involved in the mediation of anti-oncogenic and chemopreventive effects of omega-3 PUFAs.

Publication Types: Research Support, N.I.H., Extramural

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=19969553&dopt=ExternalLink

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19: Cancer Causes Control. 2010 Mar;21(3):347-55.

Prospective studies of dietary alpha-linolenic acid intake and prostate cancer risk: a meta-analysis.

Carayol M, Grosclaude P, Delpierre C.

INSERM U, Toulouse, France. marioncarayol@yahoo.fr

Individual-based studies that investigated the relation between dietary alpha-linolenic acid (ALA) intake and prostate cancer risk have shown inconsistent results. We carried out a meta-analysis of prospective studies to examine this association. We systematically searched studies published up to December 2008. Log relative risks (RRs) were weighted by the inverse of their variances to obtain a pooled estimate with its 95% confidence interval (CI). We identified five prospective studies that met our inclusion criteria and reported risk estimates by categories of ALA intake. Comparing the highest to the lowest ALA intake category, the pooled RR was 0.97 (95% CI:0.86-1.10) but the association was heterogeneous. Using the reported numbers of cases and non-cases in each category of ALA intake, we found that subjects who consumed more than 1.5 g/day of ALA compared with subjects who consumed less than 1.5 g/day had a significant decreased risk of prostate cancer: RR = 0.95 (95% CI:0.91-0.99). Divergences in results could partly be explained by differences in sample sizes and adjustment but they also highlight limits in dietary ALA assessment in such prospective studies. Our findings support a weak protective association between dietary ALA intake and prostate cancer risk but further research is needed to conclude on this question.

Publication Types: Meta-Analysis Review

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=19921446&dopt=ExternalLink

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20: 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.

Publication Types: Clinical Trial, Phase II Research Support, Non-U.S. Gov't

Links http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=PubMed&list_uids=19920822&dopt=ExternalLink

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MedASq (the Medline Abstract Squeezer) is © Ernesto de Bernardis 2002. Thanks to Eric Mueller for his on-the-fly ZIP creation code, to Google for automatic translations, to the NCBI people who wrote the new Entrez Utilities, and to the USA Government and NLM who allowed free access to the PubMed database [Disclaimer]. The URL of this site is http://www.debernardis.it/medasq.php; my home page is in http://www.debernardis.it