IntroductionComplementary and Alternative Medicine (CAM) include a wide range of products (herbs, vitamins, minerals, and probiotics) and medical practices, developed outside of the mainstream Western medicine. Patients with cancer are more likely to resort to CAM first or then in their disease history; the potential side effects as well as the costs of such practices are largely underestimated.Patients and methodWe conducted a descriptive survey in five Italian hospitals involving 468 patients with different malignancies. The survey consisted of a forty-two question questionnaire, patients were eligible if they were Italian-speaking and receiving an anticancer treatment at the time of the survey or had received an anticancer treatment no more than three years before participating in the survey.RESULTSOf our patients, 48.9% said they use or have recently used CAM. The univariate analysis showed that female gender, high education, receiving treatment in a highly specialized institute and receiving chemotherapy are associated with CAM use; at the multivariate analysis high education (Odds Ratio, (OR): 1.96 95% Confidence Interval, CI, 1.27-3.05) and receiving treatment in a specialized cancer center (OR: 2.75 95% CI, 1.53-4.94) were confirmed as risk factors for CAM use.ConclusionRoughly half of our patients receiving treatment for cancer use CAM. It is necessary that health professional explore the use of CAM with their cancer patients, educate them about potentially beneficial therapies in light of the limited available evidence of effectiveness, and work towards an integrated model of health-care provision.

Background Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA‐REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of EMPA in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analysed. We aimed to evaluate the effects of EMPA on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and MyD88-related pathways resulting in anti-apoptotic and anti-fibrotic effects. Methods Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to EMPA. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studies were also performed: expression of NLRP3 inflammasome, MyD88 myddosome and p65/NF-κB associated to secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin (DOXO, n = 6), EMPA (EMPA, n = 6) or doxorubicin combined to EMPA (DOXO-EMPA, n = 6). DOXO was injected intraperitoneally. Ferroptosis and xanthine oxidase were studied before and after treatments. Cardiac function studies, including EF, FS and radial/longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were histologically studied through Picrosirius red and TUNEL assay, respectively and quantified through pro-collagen-1α1, MMP-9 and Caspase-3 expression. Tissue NLRP3, MyD88 and cytokines were also quantified before and after treatments through ELISA methods. Results Cardiomyocytes exposed to doxorubicin increased the intracellular Ca2+ content and expression of several pro-inflammatory markers associated to cell death; co-incubation with EMPA reduced significantly the magnitude of the effects. In preclinical study, EMPA increased EF and FS compared to DOXO groups (p < 0.05), prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin (RS) 30.3% in EMPA-DOXO vs 15.7% in DOXO mice; LS − 17% in EMPA-DOXO vs – 11.7% in DOXO mice (p < 0.001 for both). Significant reductions in ferroptosis, xanthine oxidase expression, cardiac fibrosis and apoptosis in EMPA associated to DOXO were also seen. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart, liver and kidneys was also seen in DOXO-EMPA group compared to DOXO (p < 0.001). Conclusion EMPA reduced ferroptosis, fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in significant improvements in cardiac functions. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.

Doxorubicin is a highly active antineoplastic agent, but its clinical use is limited because of its cardiotoxicity. Although nutraceuticals endowed with anti-inflammatory properties exert cardioprotective activity, their bioavailability and stability are inconsistent. In an attempt to address this issue, we evaluated whether bioavailable nanoemulsions loaded with nutraceuticals (curcumin and fresh and dry tomato extracts rich in lycopene) protect cardiomyoblasts (H9C2 cells) from doxorubicin-induced toxicity. Nanoemulsions were produced with a high-pressure homogenizer. H9C2 cells were incubated with nanoemulsions loaded with different nutraceuticals alone or in combination with doxorubicin. Cell viability was evaluated with a modified MTT method. The levels of the lipid peroxidation products malondialdehyde (MDA) and 4-hydroxy-2-butanone (4-HNA), and of the cardiotoxic-related interleukins IL-6, IL-8, IL-1β and IL-10, tumor necrosis factor-alpha (TNF-α), and nitric oxide were analyzed in cardiomyoblasts. The hydrodynamic size of nanoemulsions was around 100 nm. Cell viability enhancement was 35–40% higher in cardiomyoblasts treated with nanoemulsion + doxorubicin than in cardiomyoblasts treated with doxorubicin alone. Nanoemulsions also protected against oxidative stress as witnessed by a reduction of MDA and 4-HNA. Notably, nanoemulsions inhibited the release of IL-6, IL-8, IL-1β, TNF-α and nitric oxide by around 35–40% and increased IL-10 production by 25–27% versus cells not treated with emulsions. Of the nutraceuticals evaluated, lycopene-rich nanoemulsions had the best cardioprotective profile. In conclusion, nanoemulsions loaded with the nutraceuticals described herein protect against cardiotoxicity, by reducing inflammation and lipid oxidative stress. These results set the stage for studies in preclinical models.

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Background: There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy. Methods: 102 stage II high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the χ² test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS. Results: Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI ≥25 (HR: 3.69, p = 0.002). Discussion: Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer.

The aim of this study is based on the evaluation of anticancer, anti-inflammatory activities, and cellular uptake of hyaluronic acid nanohydrogel of quercetin tested alone and in combination to a macrolide derivative of rapamycin RAD001 (everolimus) on hormone-responsive breast cancer cell line MCF-7. Biological investigations were focused on the receptor mediated cellular internalization of the nanohydrogel and its abilities to reduce secretion of several cytokines (IL-8, IL-6, IL-19), VEGF, and metalloproteases (MMP-2, MMP-9) under pro-inflammatory conditions. Nanohydrogel show a CD44 dependent endocytosis with evident time dependent cytoplasmatic accumulation with abilities to reduce secretion of all cytokines of ∼60% compared to untreated cells. Combination of formulated quercetin and everolimus leads to a synergistic cytotoxic effects with a Combination Index of 0.38. These results highlights the importance of synergistic effect of the hyaluronic acid nanohydrogel of quercetin with everolimus in the regulation of human breast cancer cell proliferation and emphasize the antitumor and anti-inflammatory properties of the nanocarrier. J. Cell. Physiol. 232: 2063-2074, 2017. © 2016 Wiley Periodicals, Inc.

Among the most important traditional medicinal fungi, Ganoderma lucidum has been used as a therapeutic agent for the treatment of numerous diseases, including cancer, in Oriental countries. The aim of this study is to investigate the anti-inflammatory, anticancer and anti-metastatic activities of Ganoderma lucidum extracts in melanoma and triple-negative breast cancer cells. Ganoderma lucidum extracts were prepared by using common organic solvents; MDA-MB 231 and B16-F10 cell lines were adopted as cellular models for triple-negative breast cancer and melanoma and characterized for cell viability, wound-healing assay and measurement of cytokines secreted by cancer cells under pro-inflammatory conditions (incubation with lipopolysaccharide, LPS) and pretreatment with Ganoderma lucidum extract at different concentrations. Our study demonstrates, for the first time, how Ganoderma lucidum extracts can significantly inhibit the release of IL-8, IL-6, MMP-2 and MMP-9 in cancer cells under pro-inflammatory condition. Interestingly, Ganoderma lucidum extracts significantly also decrease the viability of both cancer cells in a time- and concentration-dependent manner, with abilities to reduce cell migration over time, which is correlated with a lower release of matrix metalloproteases. Taken together, these results indicate the possible use of Ganoderma lucidum extract for the therapeutic management of melanoma and human triple-negative breast cancer.

Glioblastoma multiforme is the most common and aggressive primary brain cancer with only ∼3% of patients surviving more than 3 years from diagnosis. Several mechanisms are involved in drug and radiation resistance to anticancer treatments and among them one of the most important factors is the tumor microenvironment status, characterized by cancer cell hypersecretion of interleukins and cytokines. The aim of our research was the synthesis of a nanocarrier of quercetin combined with temozolomide, to enhance the specificity and efficacy of this anticancer drug commonly used in glioblastoma treatment. The nanohydrogel increased the internalization and cytotoxicity of quercetin in human glioblastoma cells and, when co-delivered with temozolomide, contribute to an improved anticancer effect. The nanohydrogel loaded with quercetin had the ability to recognize CD44 receptor, a brain cancer cell marker, through an energy and caveolae dependent mechanism of internalization. Moreover, nanohydrogel of quercetin was able to reduce significantly IL-8, IL-6, and VEGF production in pro-inflammatory conditions with interesting implications on the mechanism of glioblastoma cells drug resistance. In summary, novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site-specific delivery of quercetin via CD44 receptor in glioblastoma cells. This targeted therapy lead to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.