Double-responsive hyaluronic acid-based prodrugs for efficient tumour targeting.

Hyaluronic acid (HA)-based prodrugs bearing double-responsive (acid pH or oxidation) boronates of catechol-containing drugs were used to treat xenografted human prostate tumours (LNCaP) in SCID mice. The HA prodrugs accumulated significantly only in tumours (impressively, up to 40% of the injected dose after 24 h) and in liver, with negligible - actually anti-inflammatory - consequences in the latter. A quercetin-HA prodrug significantly slowed down tumour growth, in a dose-dependent fashion and with a much higher efficacy (up to 4 times) than equivalent doses of free quercetin. In short, boronated HA appears to be a very promising platform for targeted chemotherapy.

Nano-Encapsulation of Coenzyme Q10 in Secondary and Tertiary Nano-Emulsions for Enhanced Cardioprotection and Hepatoprotection in Human Cardiomyocytes and Hepatocytes During Exposure to Anthracyclines and Trastuzumab.

INTRODUCTION: CoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance. METHODS: We tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity. RESULTS: Nano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-κB expression and Interleukin 1ß and 6 production during anticancer treatments. DISCUSSION: Anthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.

Skin Toxicities During Colorectal Cancer Chemotherapy: Incidence and Pearls of Treatment in Our Experience.

INTRODUCTION: Medical treatment of advanced colorectal cancer is effective in prolonging the survival of patients. The aim of this study was to describe the most common skin toxicities that occur in those patients, analyzing the association between the type of reaction and the different chemotherapeutic drugs; and to evaluate the importance of an outpatient dermatologic service to improve quality of life. PATIENTS AND METHODS: Seventy-two patients with skin reactions from advanced colorectal cancer chemotherapy were included. Each patient underwent physical examination and digital photographic imaging, and completed a quality-of-life questionnaire (Dermatology Life Quality Index [DLQI]). RESULTS: Papulopustular rash was the most common side effect observed. It was statistically associated with EGFRi + irinotecan, EGFRi + FOLFOX, and EGFRi. Xerosis occurred in 50% of patients during EGFRi therapy. Periungual pyogenic granuloma-like lesions occurred in 30% of patients during EGFRi therapy. Our data underline a statistically significant association between capecitabine, FOLFOX + EGFRi, FOLFIFI + EGFRi, and hand-foot syndrome (P < .001). Because none of patients treated with EGFRi alone developed this kind of reaction, we suppose that it is associated with the use of 5-fluorouracil. Fifty percent of patients receiving anti-epidermal growth factor receptor (EGFR) therapy developed trichomegaly. These data underline a statistically significant association between these reactions and this specific drug. CONCLUSION: A dermatologic visit is useful, both for the correct diagnosis of and for the adequate therapy of chemotherapy side effects. The prevention and treatment of these toxicities are important, not only to improve quality of life but also to avoid unnecessary dose reduction or interruption, which can have a negative effect on treatment outcome.

Multicenter Single-Arm, Two-Stage Phase 2 Study of Panitumumab in Patients With Cetuximab-Refractory Metastatic Colorectal Cancer: The PACER Trial.

PURPOSE: To assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Eligible patients had pretreated RAS (renin-angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity. RESULTS: Overall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash. CONCLUSION: According to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.

Resveratrol in Cancer Patients: From Bench to Bedside.

Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytoalexin that accumulates in several vegetables and fruits like nuts, grapes, apples, red fruits, black olives, capers, red rice as well as red wines. Being both an extremely reactive molecule and capable to interact with cytoplasmic and nuclear proteins in human cells, resveratrol has been studied over the years as complementary and alternative medicine (CAM) for the therapy of cancer, metabolic and cardiovascular diseases like myocardial ischemia, myocarditis, cardiac hypertrophy and heart failure. This review will describe the main biological targets, cardiovascular outcomes, physico-chemical and pharmacokinetic properties of resveratrol in preclinical and clinical models implementing its potential use in cancer patients.

Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study.

Combination chemotherapy by means of two or more drugs is prone to suppressing or discouraging the inception of multidrug resistance, exploiting the fact that diverse drugs act in different points of the cellular cycle of amplifying tumor cells. For example, the combination of gemcitabine (GMC) with quercetin (QCT) showed a synergistic effect in inhibiting the migration of pancreatic cancer cells. Consequently, herein GMC and QCT have been loaded within biodegradable nanoparticles (NPs) based on poly(lactic-co-glycolic acid), externally decorated with hyaluronic acid (HA; viz., PPHA NPs), which plays a major role in drug targeting to tumors due to its ability to specifically interact with CD44 receptor, that is overexpressed in many tumors. The produced HA-decorated NPs loaded with GMC and QCT showed an improved cytotoxicity and cellular uptake toward two cell lines of pancreatic ductal adenocarcinoma, namely Mia-PaCa-2 and PANC-1, compared with both the bare drugs and the drugs loaded in NPs which do not expose HA on the surface. HA-decorated NPs were also able to improve the anti-inflammatory properties of QCT, therefore leading to a decrease of interleukin cellular levels in both cell lines, preliminarily stimulated with lipopolysaccharides. This result is of special interest also considering the crucial role of interleukins in progression, metastatic processes, and drug resistance of human pancreas cancer cells.

Cardioprotective Effects of Nanoemulsions Loaded with Anti-Inflammatory Nutraceuticals against Doxorubicin-Induced Cardiotoxicity.

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-1ß 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-1ß, 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.

Corrigendum to "Association of Ozone with 5-Fluorouracil and Cisplatin in Regulation of Human Colon Cancer Cell Viability: In Vitro Anti-Inflammatory Properties of Ozone in Colon Cancer Cells Exposed to Lipopolysaccharides".

[This corrects the article DOI: 10.1155/2017/7414083.].

Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC.

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients.

Correction: Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences.

[This corrects the article DOI: 10.18632/oncotarget.16725.].

Treatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first-line FOLFIRI/bevacizumab: An Italian Group for the Study of Gastrointestinal Cancer phase III, randomised trial comparing two sequences of therapy in colorectal metastatic patients.

INTRODUCTION: The optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line. PATIENTS AND METHODS: mCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS). RESULTS: About 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69-1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55-1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms. CONCLUSIONS: This trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy.

Metabolic syndrome, endocrine disruptors and prostate cancer associations: biochemical and pathophysiological evidences.

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world's leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

Anticancer and Anti-Inflammatory Properties of Ganoderma lucidum Extract Effects on Melanoma and Triple-Negative Breast Cancer Treatment.

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.

Use of Complementary and Alternative Medicine (CAM) in cancer patients: An Italian multicenter survey.

INTRODUCTION: Complementary 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 METHOD: We 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. RESULTS: Of 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. CONCLUSION: Roughly 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.

Association of Ozone with 5-Fluorouracil and Cisplatin in Regulation of Human Colon Cancer Cell Viability: In Vitro Anti-Inflammatory Properties of Ozone in Colon Cancer Cells Exposed to Lipopolysaccharides.

INTRODUCTION: Ozone therapy is an effective medical treatment for different diseases like mucositis, psoriasis, acute pain, neurovascular diseases, and cancer. The aim of this study is based on the association of different ozone concentration with 5-fluorouracil and cisplatin in human colon cancer cell (HT29 cell line) in order to investigate possible anticancer synergistic effects. METHODS: HT29 cells were incubated with ozone at different concentration ranging from 10 up to 50 µg/ml at different incubation time alone or in combination with cisplatin and 5-fluorouracil. Cell viability was performed by using a modified MTT method. Anti-inflammatory studies were conducted incubating HT29 with or without 20, 30, or 50 µg/ml of ozone before exposure to lipopolysaccharides. RESULTS: Ozone alone has a time and concentration dependent cytotoxicity against HT29 cells (IC50 at 24 h: 30 µg/ml). Association of ozone with drugs increases cytotoxicity by 15-20%. Preincubation of ozone at 50 µg/ml decreases IL-8, IL-6, and IL-1ß production by 50, 56, and 70%, respectively, compared to untreated cells. CONCLUSION: These results indicated that ozone could be useful in colon cancer management in combination with 5-fluorouracil and cisplatin with significant inhibition of cytokines having a central role in colon cancer cell survival and chemoresistance.

Surface modified zeolite-based granulates for the sustained release of diclofenac sodium.

In this study, a granulate for the oral controlled delivery of diclofenac sodium (DS), an anionic sparingly soluble nonsteroidal anti-inflammatory drug, has been realized by wet granulation, using a surface modified natural zeolite (SMNZ) as an excipient. The surface modification of the zeolite has been achieved by means of a cationic surfactant, so as to allow the loading of DS through ionic interaction and bestow a control over the drug release mechanism. The granules possessed a satisfactory dosage uniformity, a flowability suitable for an oral dosage form manufacturing, along with a sustained drug release up to 9h, driven by both ion exchange and transport kinetics. Furthermore, the obtained granulate did not elicit a significant cytotoxicity and could also induce a prolonged anti-inflammatory effect on RAW264.7 cells. Taking also into account that natural zeolites are generally abundant and economic, SMNZ can be considered as an attracting alternative excipient for the production of granules with sustained release features.

Hyaluronic Acid Nanohydrogel Loaded With Quercetin Alone or in Combination to a Macrolide Derivative of Rapamycin RAD001 (Everolimus) as a New Treatment for Hormone-Responsive Human Breast 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.

Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma.

The circulating free tumor DNA (ctDNA) represents an alternative, minimally invasive source of tumor DNA for molecular profiling. Targeted sequencing with next generation sequencing (NGS) can assess hundred mutations starting from a low DNA input. We performed NGS analysis of ctDNA from 44 patients with metastatic non-small-cell lung carcinoma (NSCLC) and 35 patients with metastatic colorectal carcinoma (CRC). NGS detected EGFR mutations in 17/22 plasma samples from EGFR-mutant NSCLC patients (sensitivity 77.3%). The concordance rate between tissue and plasma in NSCLC was much lower for other mutations such as KRAS that, based on the allelic frequency and the fraction of neoplastic cells, were likely to be sub-clonal. NGS also identified EGFR mutations in plasma samples from two patients with EGFR wild type tumor tissue. Both mutations were confirmed by droplet digital PCR (ddPCR) in both plasma and tissue samples. In CRC, the sensitivity of the NGS plasma analysis for RAS mutations was 100% (6/6) in patients that had not resection of the primary tumor before blood drawing, and 46.2% (6/13) in patients with primary tumor resected before enrollment. Our study showed that NGS is a suitable method for plasma testing. However, its clinical sensitivity is significantly affected by the presence of the primary tumor and by the heterogeneity of driver mutations.

Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy.

Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcγ receptors on immune cells. Although SNPs in genes encoding Fcγ receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcγR status and cetuximab-mediated ADCC. Patients carrying the FcγRIIa H alleles 131H/Hand 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P= 0.013). Patients carrying FcγRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P= 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P= 0.05), whereas no significant difference was observed for overall survival. Twenty-eight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcγR polymorphisms and predicted cetuximab responsiveness.