Potential of Natural Phenolic Compounds against Doxorubicin-Induced Chemobrain: Biological and Molecular Mechanisms Involved.

Chemotherapy-induced cognitive impairment or "chemobrain" is a prevalent long-term complication of chemotherapy and one of the more devastating. Most of the studies performed so far to identify the cognitive dysfunctions induced by antineoplastic chemotherapies have been focused on treatment with anthracyclines, frequently administered to breast cancer patients, a population that, after treatment, shows a high possibility of long survival and, consequently, of chemobrain development. In the last few years, different possible strategies have been explored to prevent or reduce chemobrain induced by the anthracycline doxorubicin (DOX), known to promote oxidative stress and inflammation, which have been strongly implicated in the development of this brain dysfunction. Here, we have critically analyzed the results of the preclinical studies from the last few years that have evaluated the potential of phenolic compounds (PheCs), a large class of natural products able to exert powerful antioxidant and anti-inflammatory activities, in inhibiting DOX-induced chemobrain. Several PheCs belonging to different classes have been shown to be able to revert DOX-induced brain morphological damages and deficits associated with learning, memory, and exploratory behavior. We have analyzed the biological and molecular mechanisms implicated and suggested possible future perspectives in this research area.

Hyaluronic Acid-Mediated Phenolic Compound Nanodelivery for Cancer Therapy.

Phenolic compounds are bioactive phytochemicals showing a wide range of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and anticancer effects. Moreover, they are associated with fewer side effects compared to most currently used antitumor drugs. Combinations of phenolic compounds with commonly used drugs have been largely studied as an approach aimed at enhancing the efficacy of anticancer drugs and reducing their deleterious systemic effects. In addition, some of these compounds are reported to reduce tumor cell drug resistance by modulating different signaling pathways. However, often, their application is limited due to their chemical instability, low water solubility, or scarce bioavailability. Nanoformulations, including polyphenols in combination or not with anticancer drugs, represent a suitable strategy to enhance their stability and bioavailability and, thus, improve their therapeutic activity. In recent years, the development of hyaluronic acid-based systems for specific drug delivery to cancer cells has represented a pursued therapeutic strategy. This is related to the fact that this natural polysaccharide binds to the CD44 receptor that is overexpressed in most solid cancers, thus allowing its efficient internalization in tumor cells. Moreover, it is characterized by high biodegradability, biocompatibility, and low toxicity. Here, we will focus on and critically analyze the results obtained in recent studies regarding the use of hyaluronic acid for the targeted delivery of bioactive phenolic compounds to cancer cells of different origins, alone or in combination with drugs.

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.

Preparation and Study of Solid Lipid Nanoparticles Based on Curcumin, Resveratrol and Capsaicin Containing Linolenic Acid.

Linolenic acid (LNA) is the most highly consumed polyunsaturated fatty acid found in the human diet. It possesses anti-inflammatory effects and the ability to reverse skin-related disorders related to its deficiency. The purpose of this work was to encapsulate LNA in solid lipid nanoparticles (SLNs) based on curcumin, resveratrol and capsaicin for the treatment of atopic dermatitis. These compounds were first esterified with oleic acid to obtain two moonoleate and one oleate ester, then they were used for SLN matrix realization through the emulsification method. The intermediates of the esterification reaction were characterized by FT-IR and 1N-MR analysis. SLNs were characterized by dimensional analysis and encapsulation efficiency. Skin permeation studies, antioxidant and anti-inflammatory activities were evaluated. LNA was released over 24 h from nanoparticles, and resveratrol monooleate-filled SLNs exhibited a good antioxidant activity. The curcumin-based SLNs loaded or not with LNA did not induce significant cytotoxicity in NCTC 2544 and THP-1 cells. Moreover, these SLNs loaded with LNA inhibited the production of IL-6 in NCTC 2544 cells. Overall, our data demonstrate that the synthesized SLNs could represent an efficacious way to deliver LNA to skin cells and to preserve the anti-inflammatory properties of LNA for the topical adjuvant treatment of atopic dermatitis.

New Insights on the Effects of Dietary Omega-3 Fatty Acids on Impaired Skin Healing in Diabetes and Chronic Venous Leg Ulcers.

Long-chain Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) are widely recognized as powerful negative regulators of acute inflammation. However, the precise role exerted by these dietary compounds during the healing process is still largely unknown, and there is increasing interest in understanding their specific effects on the implicated cells/molecular factors. Particular attention is being focused also on their potential clinical application in chronic pathologies characterized by delayed and impaired healing, such as diabetes and vascular diseases in lower limbs. On these bases, we firstly summarized the current knowledge on wound healing (WH) in skin, both in normal conditions and in the setting of these two pathologies, with particular attention to the cellular and molecular mechanisms involved. Then, we critically reviewed the outcomes of recent research papers investigating the activity exerted by Omega-3 PUFAs and their bioactive metabolites in the regulation of WH in patients with diabetes or venous insufficiency and showing chronic recalcitrant ulcers. We especially focused on recent studies investigating the mechanisms through which these compounds may act. Considerations on the optimal dietary doses are also reported, and, finally, possible future perspectives in this area are suggested.

Characterization of a hyaluronic acid and folic acid-based hydrogel for cisplatin delivery: Antineoplastic effect in human ovarian cancer cells in vitro.

We successfully prepared and characterized a hyaluronic acid- and folic acid-based hydrogel for the delivery of cisplatin (GEL-CIS) with the aim to induce specific and efficient incorporation of CIS into ovarian cancer (OC) cells, improve its antineoplastic effect and avoid CIS-resistance. The slow and controlled release of the drug from the polymeric network and its swelling degree at physiologic pH suggested its suitability for CIS delivery in OC. We compared here the effects of pure CIS to that of GEL-CIS on human OC cell lines, either wild type or CIS-resistant, in basal conditions and in the presence of macrophage-derived conditioned medium, mimicking the action of tumor-associated macrophages in vivo. GEL-CIS inhibited OC cell growth and migration more efficiently than pure CIS and modulated the expression of proteins involved in the Epithelial Mesenchymal Transition, a process playing a key role in OC metastatic spread and resistance to CIS.

Recent Advances in Nanotechnology for the Treatment of Melanoma.

Melanoma is one of the most aggressive forms of skin cancer, with few possibilities for therapeutic approaches, due to its multi-drug resistance and, consequently, low survival rate for patients. Conventional therapies for treatment melanoma include radiotherapy, chemotherapy, targeted therapy, and immunotherapy, which have various side effects. For this reason, in recent years, pharmaceutical and biomedical research has focused on new sito-specific alternative therapeutic strategies. In this regard, nanotechnology offers numerous benefits which could improve the life expectancy of melanoma patients with very low adverse effects. This review aims to examine the latest advances in nanotechnology as an innovative strategy for treating melanoma. In particular, the use of different types of nanoparticles, such as vesicles, polymers, metal-based, carbon nanotubes, dendrimers, solid lipid, microneedles, and their combination with immunotherapies and vaccines will be discussed.

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.

Xanthan gum-based materials for omega-3 PUFA delivery: Preparation, characterization and antineoplastic activity evaluation.

Xanthan gum-based microspheres and hydrogels, useful for targeted colorectal release of omega-3 polyunsaturated fatty acids (PUFAs), were successfully prepared and characterized. In particular, the microsphere size, as well as the high hydrogel swelling degree at pH 7.4, and the omega-3 PUFA loading efficiency of both the materials suggested their suitability for colorectal delivery. Moreover, the antioxidant efficiency of the xanthan gum based materials suggests their ability to protect the omega-PUFA cargo. We demonstrated that α-linolenic acid (ALA 18:3ω-3) carried by the materials increased significantly its ability to reduce colorectal cancer cell growth in vitro. On the contrary, docosahexaenoic acid (DHA, 22:6ω-3) enclosed in the hydrogel formulation did not enhance its already high anti-neoplastic potential. The improved anti-neoplastic efficacy of ALA enclosed in both the xanthan gum-based formulations further supports the hypothesis of a potential use of this omega-3 PUFA as a suitable and more sustainable alternative to the fish-derived DHA.

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.

Long-chain n-3 PUFA against breast and prostate cancer: Which are the appropriate doses for intervention studies in animals and humans?

The potential antineoplastic effect of the long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) remains a highly controversial issue. Numerous animal studies have supported the anticancer role of these dietary fatty acids, whereas conflicting results have been obtained in population studies, and only a few intervention human trials have been so far performed. In view of the possibility that the anticancer effects may be maximally observed within a defined range of EPA and DHA doses, herein we critically review the results and doses used in both animal studies and human clinical trials focusing on the possible n-3 PUFA protective effects against breast and prostate cancer. Our main aim is to identify the EPA and/or DHA ranges of doses needed to obtain clear anticancer effects. This may be of great help in designing future animal studies, and also in understanding the most appropriate dose for further human intervention studies. Moreover, since the healthy effects of these fatty acids have been strictly related to their increased incorporation in plasma and tissue lipids, we also examine and discuss the incorporation changes following the administration of the effective anticancer EPA and/or DHA doses in animals and humans.

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.