Nutraceutical-Based Nanoformulations for Breast and Ovarian Cancer Treatment.

Different strategies have been investigated for a more satisfactory treatment of advanced breast cancer, including the adjuvant use of omega-3 polyunsaturated fatty acids (PUFAs). These nutritional compounds have been shown to possess potent anti-inflammatory and antiangiogenic activities, the capacity to affect transduction pathways/receptors involved in cell growth and to reprogram tumor microenvironment. Omega-3 PUFA-containing nanoformulations designed for drug delivery in breast cancer were shown to potentiate the effects of enclosed drugs, enhance drug delivery to target sites, and minimize drug-induced side effects. We have critically analyzed here the results of the most recent studies investigating the effects of omega-3 PUFA-containing nanoformulations in breast cancer. The anti-neoplastic efficacy of omega-3 PUFAs has also been convincingly demonstrated by using preclinical in vivo models of ovarian cancer. The results obtained are critically analyzed here and seem to provide a sufficient rationale to move to still lacking interventional clinical trials, as well as to evaluate possible advantages of enclosing omega-3 PUFAs to drug-delivery nanosystems for ovarian cancer. Future perspectives in this area are also provided.

The Combination of Sulforaphane and Fernblock® XP Improves Individual Beneficial Effects in Normal and Neoplastic Human Skin Cell Lines.

Plenty of evidence supports the health effects exerted by dietary supplements containing phytochemicals, but the actual efficacy and safety of their combinations have been seldom experimentally evaluated. On this basis, we investigated in vitro the antioxidant/antineoplastic efficacy and anti-aging activity of a dietary supplement containing sulforaphane (SFN), a sulfur-isothiocyanate present in broccoli, combined with the patented extract Fernblock® XP (FB), obtained from the tropical fern Polypodium leucotomos. We evaluated the effect of SFN and FB, alone or in combination, on migration ability, matrix metalloproteinases (MMP) production, neoangiogenic potential and inflammasome activation in human WM115 and WM266-4 melanoma cells. Moreover, the effects on MMPs and reactive oxygen species production, and IL-1ß secretion were studied in human normal keratinocytes. The SFN/FB combination inhibited melanoma cell migration in vitro, MMP-1, -2, -3, and -9 production, inflammasome activation and IL-1ß secretion more efficiently than each individual compound did. In normal keratinocytes, SFN/FB was more efficient than SFN or FB alone in inhibiting MMP-1 and -3 production and IL-1ß secretion in the presence of a pro-inflammatory stimulus such as TNF-α. The potential use of SFN/FB based supplements for the prevention of skin aging and as adjuvants in the treatment of advanced melanoma is suggested.

Omega-3 PUFA Responders and Non-Responders and the Prevention of Lipid Dysmetabolism and Related Diseases.

The long-chain omega-3 polyunsaturated fatty acids (LC-omega-3 PUFAs) eicosapentaenoic acid and docosahexaenoic acid are the most popular dietary supplements recommended for the prevention/management of lipid dysmetabolisms and related diseases. However, remarkable inconsistencies exist among the outcomes of the human intervention studies in this field, which contrast with the impressive homogeneity of positive results of most of the preclinical studies. In the present review, we will firstly examine a series of factors-such as background diet composition, gut microbiota and genetic/epigenetic variants, which may lie beneath these inconsistencies. Moreover, we will discuss the recent advance in the knowledge of possible specific biomarkers (genetic-, epigenetic- and microbiota-related) that are being investigated with the goal to apply them in a personalized supplementation with omega-3 PUFAs. We will also consider the possibility of using already available parameters (Omega-3 index, Omega-6 PUFA/Omega-3 PUFA ratio) able to predict the individual responsiveness to these fatty acids and will discuss the optimal timing for their use. Finally, we will critically examine the results of those human studies that have already adopted the distinction of the subjects into omega-3 PUFA responders and non-responders and will discuss the advantage of using such an approach.

Anti-Irritant and Anti-Inflammatory Effects of DHA Encapsulated in Resveratrol-Based Solid Lipid Nanoparticles in Human Keratinocytes.

We recently found that the dietary long chain omega-3 polyunsaturated fatty acid (LC-ω-3 PUFA), docosahexaenoic acid (DHA), showed enhanced antineoplastic activity against colon cancer cells if encapsulated in resveratrol-based solid lipid nanoparticles (RV-SLNs). In the present study, we investigated whether the DHA enclosed in RV-SLNs (DHA-RV-SLNs) could have the potential of attenuating irritation and inflammation caused by environmental factors at the skin level. To this aim, we used two keratinocyte lines (HaCaT and NCTC 2544 cells) and exposed them to the cytotoxic action of the surfactant, sodium dodecyl sulfate (SDS), as an in vitro model of irritation, or to the pro-inflammatory activity of the cytokine TNF-α. We found that DHA enclosed in RV-SLNs significantly enhanced its ability to contrast the cytotoxic effect of SDS and to inhibit the SDS- and TNF-α-induced production of the inflammatory cytokines IL-1ß, IL-6, and 1 MCP-1, in the two keratinocyte cell lines, as well as the NLRP3 inflammasome activation. Moreover, it more efficiently reduced the upsurge of reactive oxygen species (ROS) levels obtained in the presence of a pro-oxidant (H2O2). Overall, our findings suggest the possibility that a sustained dietary supplementation with DHA-RV-SLNs could efficiently protect skin from the pro-irritant and pro-inflammatory activity of environmental attacks.

Nanomedicine-based formulations containing ω-3 polyunsaturated fatty acids: potential application in cardiovascular and neoplastic diseases.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are dietary factors involved in the prevention of cardiovascular, inflammatory, and neoplastic diseases. A multidisciplinary approach - based on recent findings in nutritional science, lipid biochemistry, biotechnology, and biology of inflammation and cancer - has been recently employed to develop ω-3 PUFA-containing nanoformulations with an aim to protect these fatty acids from degradation, increase their bioavailability and delivery to target tissues, and, thus, enhance their bioactivity. In some cases, these nanoformulations were designed to administer ω-3 PUFAs in combination with other nutraceuticals or conventional/innovative drugs. The aim of this strategy was to increase the activities of the compounds contained in the nanoformulation and to reduce the adverse effects often induced by drugs. We herein analyze the results of papers evaluating the potential use of ω-3 PUFA-containing nanomaterials in fighting cardiovascular diseases and cancer. Future directions in this field of research are also provided.

Combination of ω-3 fatty acids and cisplatin as a potential alternative strategy for personalized therapy of metastatic melanoma: an in-vitro study.

The recently developed therapeutic strategies have led to unprecedented improvements in the control of metastatic melanoma and in the survival of specific subgroups of patients. However, drug resistance, low response rates, and undesired side effects make these treatments not suitable or tolerable for all the patients, and chemotherapeutic treatments appear still indispensable, at least for subgroups of patients. New combinatory strategies are also under investigation as tailored treatments or salvage therapies, including combined treatments of immunotherapy with conventional chemotherapy. On this basis, and in consideration of the antineoplastic properties of ω-3 polyunsaturated fatty acids, we have here investigated the potential of these bioactive dietary factors to revert the resistance frequently exhibited by this form of cancer to cisplatin (CDDP, cis-diamminedichloroplatinum). We demonstrated that docosahexenoic acid (DHA, 22:6ω-3) sensitizes the cells to the CDDP-induced inhibition of cell growth and migration by reverting CDDP effects on DNA damage and ERCC1 expression, as well as on the DUSP6 and p-ERK expressions, which regulate ERCC1 activation upwardly. In line, DUSP6 gene silencing prevented the effect of DHA, confirming that DHA acted on the DUSP6/p-ERK/ERCC1 repair pathways to sensitize melanoma cells to the anticancer effect of CDDP. Similar effects were obtained also with eicosapentaenoic acid (20:5ω-3). Overall, our findings suggest that the combination of CDDP treatment with a dietary supplementation with ω-3 polyunsaturated fatty acids could potentially represent a new therapeutic strategy for overcoming CDDP resistance in metastatic melanoma.

Omega-3 PUFA Loaded in Resveratrol-Based Solid Lipid Nanoparticles: Physicochemical Properties and Antineoplastic Activities in Human Colorectal Cancer Cells In Vitro.

New strategies are being investigated to ameliorate the efficacy and reduce the toxicity of the drugs currently used in colorectal cancer (CRC), one of the most common malignancies in the Western world. Data have been accumulated demonstrating that the antineoplastic therapies with either conventional or single-targeted drugs could take advantage from a combined treatment with omega-3 polyunsaturated fatty acids (omega-3 PUFA). These nutrients, shown to be safe at the dosage generally used in human trials, are able to modulate molecules involved in colon cancer cell growth and survival. They have also the potential to act against inflammation, which plays a critical role in CRC development, and to increase the anti-cancer immune response. In the present study, omega-3 PUFA were encapsulated in solid lipid nanoparticles (SLN) having a lipid matrix containing resveratrol esterified to stearic acid. Our aim was to increase the efficiency of the incorporation of these fatty acids into the cells and prevent their peroxidation and degradation. The Resveratrol-based SLN were characterized and investigated for their antioxidant activity. It was observed that the encapsulation of omega-3 PUFA into the SLN enhanced significantly their incorporation in human HT-29 CRC cells in vitro, and their growth inhibitory effects in these cancer cells, mainly by reducing cell proliferation.

Long-chain omega-3 fatty acids and cancer: any cause for concern?

PURPOSE OF REVIEW: Recently, concerns have been raised with regard to the recommended doses of marine long-chain omega-3 polyunsaturated fatty acids (LC-omega-3 PUFAs) especially in relation to cancer risk and treatment. There is urgent need to clarify this point. This review considers the most recent evidence related to the potential risk of developing cancer with high LC-omega-3 PUFA intakes, and possible research strategies to better elucidate this matter. RECENT FINDINGS: The latest published recommendations have still highlighted the usefulness of an increased dietary intake of LC-omega-3 PUFAs for the prevention of some cardiovascular diseases. However, LC-omega-3 PUFAs have been related to the potential development and progression of cancer, and considerable debate exists on this issue. SUMMARY: The use of biomarkers reflecting the intake of LC-omega-3 PUFAs as cancer risk markers is discussed, as well as the possibility that the reported beneficial/deleterious effects may be confined to specific subpopulations on the basis of genetic, metabolic, and nutritional characteristics. Recent advances on new strategies for a safer intake of LC-omega-3 PUFAs will be considered, as their dietary sources may be contaminated by toxic/carcinogenic compounds. Potentially future directions in this important research area are also discussed.

Protective Effects of ω-3 PUFA in Anthracycline-Induced Cardiotoxicity: A Critical Review.

It has been demonstrated that ω-3 polyunsaturated fatty acids (ω-3 PUFA) may exert a beneficial role as adjuvants in the prevention and treatment of many disorders, including cardiovascular diseases and cancer. Particularly, several in vitro and in vivo preclinical studies have shown the antitumor activity of ω-3 PUFA in different kinds of cancers, and several human studies have shown that ω-3 PUFA are able to decrease the risk of a series of cardiovascular diseases. Several mechanisms have been proposed to explain their pleiotropic beneficial effects. ω-3 PUFA have also been shown to prevent harmful side-effects (including cardiotoxicity and heart failure) induced by conventional and innovative anti-cancer drugs in both animals and patients. The available literature regarding the possible protective effects of ω-3 PUFA against anthracycline-induced cardiotoxicity, as well as the mechanisms involved, will be critically discussed herein. The study will analyze the critical role of different levels of ω-3 PUFA intake in determining the results of the combinatory studies with anthracyclines. Suggestions for future research will also be considered.

Modulation of Ras/ERK and Phosphoinositide Signaling by Long-Chain n-3 PUFA in Breast Cancer and Their Potential Complementary Role in Combination with Targeted Drugs.

A potential complementary role of the dietary long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFA) in combination with innovative mono-targeted therapies has recently been proposed. These compounds are thought to act pleiotropically to prevent the development and progression of a variety of cancers, including breast cancer. We hereinafter critically analyze the reports investigating the ability of LCn-3 PUFA to modulate the Ras/ERK and the phosphoinositide survival signaling pathways often aberrantly activated in breast cancer and representing the main targets of innovative therapies. The in vitro or in vivo animal and human interventional studies published up to January 2017 investigating the effects of LCn-3 PUFA on these pathways in normal and cancerous breast cells or tissues were identified through a systematic search of literature in the PubMed database. We found that, in most cases, both the in vitro and in vivo studies demonstrated the ability of LCn-3 PUFA to inhibit the activation of these pro-survival pathways. Altogether, the analyzed results strongly suggest a potential role of LCn-3 PUFA as complementary agents in combination with mono-targeted therapies. Moreover, the results indicate the need for further in vitro and human interventional studies designed to unequivocally prove the potential adjuvant role of these fatty acids.

Role of ß-catenin signaling in the anti-invasive effect of the omega-3 fatty acid DHA in human melanoma cells.

BACKGROUND: We previously found that docosahexaenoic acid (DHA), a dietary polyunsaturated fatty acid present at high level in fatty fish, inhibited cell growth and induced differentiation of melanoma cells in vitro by increasing nuclear ß-catenin content. An anti-neoplastic role of nuclear ß-catenin was suggested in melanoma, and related to the presence in the melanocyte lineage of the microphtalmia transcription factor (MITF), which interferes with the transcription of ß-catenin/TCF/LEF pro-invasive target genes. OBJECTIVE: In the present work we investigated if DHA could inhibit the invasive potential of melanoma cells, and if this effect could be related to DHA-induced alterations of the Wnt/ß-catenin signaling, including changes in MITF expression. METHODS: WM115 and WM266-4 human melanoma, and B16-F10 murine melanoma cell lines were used. Cell invasion was evaluated by Wound Healing and Matrigel transwell assays. Protein expression was analyzed by Western Blotting and ß-catenin phosphorylation by immunoprecipitation. The role of MITF in the anti-invasive effect of DHA was analyzed by siRNA gene silencing. RESULTS: We found that DHA inhibited anchorage-independent cell growth, reduced their migration/invasion in vitro and down-regulated several Matrix Metalloproteinases (MMP: MMP-2, MT1-MMP and MMP-13), known to be involved in melanoma invasion. We related these effects to the ß-catenin increased nuclear expression and PKA-dependent phosphorylation, as well as to the increased expression of MITF. CONCLUSION: The data obtained further support the potential role of dietary DHA as suppressor of melanoma progression to invasive malignancy through its ability to enhance MITF expression and PKA-dependent nuclear ß-catenin phosphorylation.

How plausible is the use of dietary n-3 PUFA in the adjuvant therapy of cancer?

Considerable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.

Epigenetic regulation of gene expression and M2 macrophage polarization as new potential omega-3 polyunsaturated fatty acid targets in colon inflammation and cancer.

INTRODUCTION: It has become increasingly clear that dietary habits may affect the risk/progression of chronic diseases with a pathogenic inflammatory component, such as colorectal cancer. Considerable attention has been directed toward the ability of nutritional agents to target key molecular pathways involved in these inflammatory-related diseases. AREAS COVERED: ω-3 Polyunsaturated fatty acids (PUFA) and their oxidative metabolites have attracted considerable interest as possible anti-inflammatory and anti-cancer agents, especially in areas such as the large bowel, where the influence of orally introduced substances is high and tumors show deranged PUFA patterns. On this basis, we have analyzed pre-clinical findings that have recently revealed new insight into the molecular pathways targeted by ω-3 PUFA. EXPERT OPINION: The findings analyzed herein demonstrate that ω-3 PUFA may exert beneficial effects by targeting the epigenetic regulation of gene expression and altering M2 macrophage polarization during the inflammatory response. These mechanisms need to be better explored in the large bowel, and further studies could better clarify their role and the potential of dietary interventions with ω-3 PUFA in the large bowel. The epigenomic mechanism is discussed in view of the potential of ω-3 PUFA to enhance the efficacy of other agents used in the therapy of colorectal cancer.

Reduction of Oxidative/Nitrosative Stress in Brain and its Involvement in the Neuroprotective Effect of n-3 PUFA in Alzheimer's Disease.

Plenty of evidence has shown that an enhanced oxidative or nitrosative stress may play a central role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). The suppressive effect of n-3 polyunsaturated fatty acids (n-3 PUFA) against oxidative/nitrosative stressinduced injury in nervous tissues has recently received increasing interest. A number of human experimental studies have concurred to demonstrate that they may exert a substantial preventive role, especially in the very early phase of mild cognitive impairment (MCI) preceding AD. It has been suggested that they may exert an indirect antioxidant/anti-nitrosative role by modulating the expression/ activity of several proteins involved in the modulation of oxidative stress in nervous tissues. In particular, recent data have supported the hypothesis that in the early phase of MCI the light to moderate oxidative stress triggered by not cytotoxic doses of n-3 PUFA can positively regulate the transcriptional activity of nuclear factor erythroid 2-related factor 2 (Nrf2). This may result in the induced expression of heme oxygenase-1 (HO-1) and other antioxidant proteins transcriptionally regulated by Nrf2. Alternatively, the anti-inflammatory and antioxidant/anti-nitrosative effects of n-3 PUFA have been lately related to their ability to blunt microglia persistent activation occurring during chronic inflammation involved in the pathogenesis of neurodegenerative diseases. Evidences have been presented that n-3 PUFA may convert microglia from the macrophage M1 to an M2 phenotype showing lower production of neurotoxicoxidative factors and enhanced phagocytic activity toward Aß peptide, or even to a further phenotype with neurotrophic/ protective properties.

Omega-3 Polyunsaturated Fatty Acids: The Way Forward in Times of Mixed Evidence.

Almost forty years ago, it was first hypothesized that an increased dietary intake of omega-3 polyunsaturated fatty acids (PUFA) from fish fat could exert protective effects against several pathologies. Decades of intense preclinical investigation have supported this hypothesis in a variety of model systems. Several clinical cardiovascular studies demonstrated the beneficial health effects of omega-3 PUFA, leading medical institutions worldwide to publish recommendations for their increased intake. However, particularly in recent years, contradictory results have been obtained in human studies focusing on cardiovascular disease and the clinical evidence in other diseases, particularly chronic inflammatory and neoplastic diseases, was never established to a degree that led to clear approval of treatment with omega-3 PUFA. Recent data not in line with the previous findings have sparked a debate on the health efficacy of omega-3 PUFA and the usefulness of increasing their intake for the prevention of a number of pathologies. In this review, we aim to examine the controversies on the possible use of these fatty acids as preventive/curative tools against the development of cardiovascular, metabolic, and inflammatory diseases, as well as several kinds of cancer.

Antioxidant and anti-inflammatory effects of selected natural compounds contained in a dietary supplement on two human immortalized keratinocyte lines.

Several advantages may derive from the use of dietary supplements containing multiple natural antioxidants and/or anti-inflammatory agents. At present, however, there is scarce information on the properties and potential of combined supplements. To fill the gap, the antioxidant and anti-inflammatory activities exerted by a combination of seven natural components (coenzyme Q10, krill oil, lipoic acid, resveratrol, grape seed oil, α-tocopherol, and selenium) contained in a dietary supplement used for the prevention of skin disorders were investigated in vitro. Each component was administered, alone or in combination, to human keratinocytes, and the inhibition of Reactive Oxygen Species production and lipid peroxidation as well as the ability to reduce inflammatory cytokine secretion and to modulate Nuclear Factor-κB pathway was evaluated. The combination exhibited high antioxidant activity and in specific conditions the combination's efficiency was higher than that of the most powerful components administered individually. Moreover, the combination showed remarkable anti-inflammatory properties. It reduced more efficiently than each component the secretion of Monocyte Chemoattractant Protein-1, a crucial cytokine for the development of chronic inflammation in skin, and inhibited Nuclear Factor-κB molecular pathway. Overall, our findings suggest that the combined formulation may have the potential to powerfully inhibit oxidative stress and inflammation at skin level.

Potential of long-chain n-3 polyunsaturated fatty acids in melanoma prevention.

The possible antineoplastic activity of dietary long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) has been supported by ample preclinical studies that have identified a number of molecular factors and pathways affected by these fatty acids and involved in cell growth, apoptosis, invasion, and angiogenesis. The aim of this critical review is to assess the current state of knowledge on the potential anticancer effects of LC n-3 PUFAs against malignant melanoma, one of the most common cancers among Western populations. The results of preclinical as well as human observational and interventional studies investigating the effects of LC n-3 PUFAs in melanoma were examined. Overall, the analysis of the literature reveals that, even though a large body of information is available, further effort is needed to identify the main molecular targets of LC n-3 PUFAs in melanoma. Moreover, additional well-designed human observational studies are essential to shed further light on the issue. The results of these studies could provide support and specific information for the development of clinical studies, especially those performed in combination with conventional or innovative antineoplastic therapies.

Experimental evidence of ω-3 polyunsaturated fatty acid modulation of inflammatory cytokines and bioactive lipid mediators: their potential role in inflammatory, neurodegenerative, and neoplastic diseases.

A large body of evidence has emerged over the past years to show the critical role played by inflammation in the pathogenesis of several diseases including some cardiovascular, neoplastic, and neurodegenerative diseases, previously not considered inflammation-related. The anti-inflammatory action of ω-3 polyunsaturated fatty acids (PUFAs), as well as their potential healthy effects against the development and progression of the same diseases, has been widely studied by our and others' laboratories. As a result, a rethinking is taking place on the possible mechanisms underlying the beneficial effects of ω-3 PUFAs against these disorders, and, in particular, on the influence that they may exert on the molecular pathways involved in inflammatory process, including the production of inflammatory cytokines and lipid mediators active in the resolving phase of inflammation. In the present review we will summarize and discuss the current knowledge regarding the modulating effects of ω-3 PUFAs on the production of inflammatory cytokines and proresolving or protective lipid mediators in the context of inflammatory, metabolic, neurodegenerative, and neoplastic diseases.

EPA and DHA differentially affect in vitro inflammatory cytokine release by peripheral blood mononuclear cells from Alzheimer's patients.

It has been hypothesized that pro-inflammatory cytokines may play a pathogenic role in Alzheimer's disease (AD), and that n-3 polyunsaturated fatty acids may be protective against the development and progression of this disease. A reduced release of inflammatory cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from AD patients dietary supplemented with a mixture of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) was recently reported. On this basis, we investigated the possible differential effects of the two purified fatty acids on inflammatory cytokine release, a subject still not explored, even though of great pharmacological interest. We treated in vitro phytohaemagglutinin (PHA)- or LPS-stimulated PBMCs from AD patients and age-matched healthy controls (HCs) with purified EPA or DHA. Higher pro- to anti-inflammatory cytokine ratios, indicative of a pro-inflammatory profile, were observed in PHA-stimulated PBMCs from AD patients in basal conditions. The addition of both EPA and DHA markedly reduced the cytokine release, with DHA showing always a more prominent effect than EPA. However, whereas DHA reduced only the high IL-1ß/IL-10 ratio, EPA was able to reduce also the IL-6/IL-10 ratio. In stimulated PMBCs from HCs the reducing effect on cytokine release was not always observed, or observed at a lower degree. In conclusion, whereas DHA appeared more powerful in inhibiting each single inflammatory cytokine, the proinflammatory profile of the AD patients' cells was better reverted by EPA to a profile more similar to that found in HCs. A combination of both the fatty acids, seems to be still the best solution.

Dietary n-3 polyunsaturated fatty acids and the paradox of their health benefits and potential harmful effects.

There is some evidence to support the toxicity of polyunsaturated fatty acids (PUFAs) and their oxidative products, suggesting their involvement in the pathogenesis of different chronic diseases, including cancer. It has been shown that products of PUFA oxidation may exert a carcinogenic action by forming mutagenic adducts with DNA. However, a large amount of evidence accumulated over several decades has indicated the beneficial effects of administration of n-3 PUFAs in the prevention and therapy of a series of diseases. In particular, there is much evidence that n-3 PUFAs exert anti-inflammatory and antineoplastic effects, whereas n-6 PUFAs promote inflammation and carcinogenesis. In our tissues, both of the two classes of PUFAs can be converted into bioactive products, incorporated into membrane phospholipids or bound to membrane receptors, where they may alter, often in opposite ways, transduction pathways and affect important biological processes, such as cell death and survival, inflammation, and neo-angiogenesis. In the present review, we intend to shed light on the paradox of the coexisting healthy and toxic effects of n-3 PUFAs, focusing on their possible pro-oxidant cytotoxic and carcinogenic effect, in order to understand if their increased intake, recommended by a number of health agencies worldwide and promoted by nutraceutical producers, may or may not represent a hazard to human health.