Epidemiological studies have linked fish oil consumption to a decreased incidence of cancer. The anticancer effects of fish oil are mostly attributed to its content of omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, DHA, because of its unique effect of altering membrane composition, is often regarded as the major omega-3 fatty acid involved in anticancer activity. Although use of DHA as an anticancer drug to prevent or treat human cancer in clinical settings has not yet been well established, recent studies suggest that DHA can be very effective as an adjuvant with other anticancer agents. In this article, we present studies that show the role of DHA in improving anticancer drug efficacy. Several in vitro and animal studies suggest that combining DHA with other anticancer agents often improves efficacy of anticancer drugs and also reduces therapy-associated side effects. Incorporation of DHA in cellular membranes improves drug uptake, whereas increased lipid peroxidation is another mechanism for DHA-mediated enhanced efficacy of anticancer drugs. In addition, several intracellular targets including cyclooxygenase-2, nuclear factor kappa B, peroxisome proliferator-activated receptor gamma, mitogen-activated protein kinase, AKT, and BCL-2/BAX are found to play an important role in DHA-mediated additive or synergistic interaction with anticancer drugs. The data suggest that DHA is a safe, natural compound that can greatly improve the anticancer properties of anticancer drugs. Use of DHA with anticancer treatments provides an avenue to therapeutic improvement that involves less risk or side effects for patients and reduced regulatory burden for implementation.
BackgroundThe major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice.MethodsWe used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey’s post hoc procedure.ResultsAnalysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of “PAM50” genes in the SK-BR-3 cell line from an ER-/Her-2+ to that resembling a “normal-like” phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin.ConclusionsThe SK-BR-3 cells and DMBA-induced tumors, both with an ER- and Her-2+ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.
Epidemiological data have shown an association of the intake of industrial produced trans fatty acids (TFA) and sudden cardiac death. The present study examines the impact of elaidic acid (t18:1n-9) and linoelaidic acid (t18:2n-6) on the human aortic endothelial cell functional response. Trans fatty acids predominately incorporated into the phospholipid component while only a minute fraction of the total fatty acids (FA) incorporated into triacylglycerol. Trans fatty acids incorporated into the plasma membranes at the expense of the saturated-FA, stearic, palmitic, and to a lesser extent, myristic acid. Both t18:1n-9 and t18:2n-6 induced a pro-inflammatory response by elevating surface expression of intercellular adhesion molecule-1 (ICAM-1). Neither oleic nor linoleic evoked a pro-inflammatory phenotype under the maximal 50 µM treatments. Both TFA and stearic acid increased phosphorylation of the ICAM-1 transcriptional regulator, nuclear factor-κβ (NF-κβ), while oleic and linoleic acids did not appear to alter the phosphorylation status. Elaidic acid minimally affected endothelial cell growth, whereas linoelaidic acid completely inhibited growth at 100 µM and imparted limited cytotoxicity up to 300 µM. Stearic acid induced cytotoxicity at concentrations above 75 µM, while oleic and linoleic acids evoked gradual dose-dependent growth inhibition with cytotoxicity occurring only at linoleic acid concentrations greater than 200 µM. In conclusion, t18:1n-9 and t18:2n-6 fatty acids effectively incorporated into the phospholipid component of endothelial cells and subsequently induce a pro-inflammatory phenotype.
There are few effective treatments of antisocial personality disorder (APD). Preliminary work suggests that the atypical antipsychotic quetiapine can decrease irritability, impulsivity, and aggressiveness. Data were collected from 4 patients with APD who were referred to a maximum-security inpatient psychiatric facility for pretrial evaluation and were treated with quetiapine. Quetiapine was effective in these patients as was indicated by a decrease in symptoms such as impulsivity, hostility, aggressiveness, irritability, and rage reactions. Typical dosage was 600 to 800 mg per day. Patients attributed their willingness to comply with quetiapine treatment to both the effectiveness of the drug and its favorable adverse-event profile. Quetiapine was successfully combined with mood stabilizers, particularly gabapentin, in patients with prominent affective instability. Quetiapine has demonstrated efficacy in aggression, impulsivity, and irritability and has proved to be an effective medication in these patients with APD. In addition, its favorable adverse-event profile makes patients willing to comply.
Lipid emulsions are made by mixing vegetable and/or fish oils with egg yolk and contain different types and amounts of fatty acids and sterols. This study assessed the effects of oral diet, soybean oil (SO)-, fish oil (FO)-, a mixture of olive and soybean oil (OOSO)-, and a mixture of fish, olive, coconut, and soybean oil (FOCS)-based emulsions on plasma triacylglycerols and plasma and tissue fatty acid and sterol content following acute and chronic intravenous administration in the guinea pig. Upon acute administration, peak triacylglycerols were highest with SO and lowest with OOSO. Upon chronic administration, the plasma triglyceride levels did not increase in any group over that of the controls. Fatty acid levels varied greatly between organs of animals on the control diets and organs of animals following acute or chronic lipid administration. Squalene levels increased in plasma following acute administration of OOSO, but plasma squalene levels were similar to control in all emulsion groups following chronic administration. Total plasma phytosterol levels were increased in the SO, OOSO, and FOCS groups following both acute and chronic infusions, whereas phytosterols were not increased following FO infusion. Total phytosterol levels were higher in liver, lung, kidney and adipose tissue following SO and OOSO. Levels were not increased in tissues after FO and FOCS infusion. These results indicate that fatty acid and sterol contents vary greatly among organs and that no one tissue reflects the fatty acid or sterol composition of other tissues, suggesting that different organs regulate these compounds differently.
Studies of human native C-reactive protein (nCRP) in mice have shown effects ranging from proatherogenic, to antiatherogenic, to no effect. It is likely that these disparities are related to (a) the use, in some studies, of contaminated nCRP, or to (b) variation in CRP levels associated with either its episodic administration or the use of CRP-transgenic mice. In our study, 12-week-old male apolipoprotein E-deficient (apoE (-/-)) mice, maintained on a Western diet, received azide- and endotoxin-free nCRP (n = 23) or placebo (n = 23) continuously via osmotic pumps (20.4 microg/day) for 4 weeks. CRP-treated and control mice developed similar atherosclerotic lesions in whole aortas (nCRP: 10.4 +/- 4.7% vs. controls: 11.7 +/- 4.4%, P = 0.76) and aortic roots (nCRP: 65.0 +/- 7.8% vs. controls: 64.7 +/- 9.7%, P = 0.94). No differences were observed in macrophage or T-lymphocyte infiltrates and there was no meaningful change in VCAM-1 or IL-6 expression, in the levels of soluble VCAM-1, or in circulating proinflammatory (IL-1 beta, IL-6, IL-12p40, IL-12p70, TNF-alpha, and INF-gamma), or anti-inflammatory (IL-4 and IL-10) cytokines. We conclude that continuous infusion of uncontaminated nCRP in apoE (-/-) mice is not associated with increased atherosclerosis, does not alter systemic or local inflammation, and does not affect endothelial activation. These observations suggest that alternative approaches to study CRP (perhaps using different pentraxins in the mouse model or using a rabbit model instead of a mouse model) are needed to evaluate the effects of pentraxins on atherosclerosis.
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