Publications by authors named "Domenica Rea"

40 Publications

The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin.

Cardiovasc Diabetol 2021 07 23;20(1):150. Epub 2021 Jul 23.

Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.

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 Ca 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 Ca 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.
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http://dx.doi.org/10.1186/s12933-021-01346-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305868PMC
July 2021

Vaccination strategy and anti - SARS-CoV-2 S titers in healthcare workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy).

Infect Agent Cancer 2021 May 12;16(1):32. Epub 2021 May 12.

Istituto Nazionale Tumori - IRCCS Fondazione Pascale, Napoli, Italy.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally, requiring the development of billions of different vaccine doses. The SARS-CoV-2 spike mRNA vaccine (named BNT162b2/Pfizer), authorized by the FDA, has shown high efficacy in preventing SARS-CoV-2 infection after administration of two doses in individuals 16 years of age and older. In the present study, we retrospectively evaluated the differences in the SARS-CoV-2 humoral immune response after vaccine administration in the two different cohorts of workers at the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): previously infected to SARS-CoV-2 subjects and not infected to SARS-CoV-2 subjects.

Methods: We determined specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S immunoassay in serum samples of 35 healthcare workers with a previous documented history of SARS-CoV-2 infection and 158 healthcare workers without, after 1 and 2 doses of vaccine, respectively. Moreover, geometric mean titers and relative fold changes (FC) were calculated.

Results: Both previously infected and not infected to SARS-CoV-2 subjects developed significant immune responses to SARS-CoV-2 after the administration of 1 and 2 doses of vaccine, respectively. Anti-S antibody responses to the first dose of vaccine were significantly higher in previously SARS-CoV-2-infected subjects in comparison to titers of not infected subjects after the first as well as the second dose of vaccine. Fold changes for subjects previously infected to SARS-CoV-2 was very modest, given the high basal antibody titer, as well as the upper limit of 2500.0 BAU/mL imposed by the Roche methods. Conversely, for naïve subjects, mean fold change following the first dose was low ([Formula: see text] =1.6), reaching 3.8 FC in 72 subjects (45.6%) following the second dose.

Conclusions: The results showed that, as early as the first dose, SARS-CoV-2-infected individuals developed a remarkable and statistically significant immune response in comparison to those who did not contract the virus previously, suggesting the possibility of administering only one dose in previously SARS-CoV-2-infected subjects. FC for previously infected subjects should not be taken into account for the generally high pre-vaccination values. Conversely, FC for not infected subjects, after the second dose, were = 3.8 in > 45.0% of vaccinees, and ≤ 3.1 in 19.0%, the latter showing a potential susceptibility to further SARS-CoV-2 infection.
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http://dx.doi.org/10.1186/s13027-021-00375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114024PMC
May 2021

Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models.

J Pers Med 2020 Oct 19;10(4). Epub 2020 Oct 19.

Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy.

Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed for cancer therapy, opening to advantages in cancer outcomes. However, several ICI-induced side effects have emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the cytotoxic and pro-inflammatory properties of Ipilimumab and Nivolumab, the underlying pathways and cytokine storm involved.

Methods: Co-cultures of human cardiomyocytes and lymphocytes were exposed to Ipilimumab or Nivolumab; cell viability and expression of leukotrienes, NLRP3, MyD88, and p65/NF-kB were performed. C57 mice were treated with Ipilimumab (15 mg/kg); analysis of fractional shortening, ejection fraction, radial and longitudinal strain were made before and after treatments through 2D-echocardiography. Expression of NLRP3, MyD88, p65/NF-kB, and 12 cytokines were analyzed in murine myocardium.

Results: Nivolumab and Ipilimumab exert effective anticancer, but also significant cardiotoxic effects in co-cultures of lymphocytes and tumor or cardiac cells. Both ICIs increased NLRP3, MyD88, and p65/NF-kB expression compared to untreated cells, however, the most pro-inflammatory and cardiotoxic effects were seen after exposure to Ipilimumab. Mice treated with Ipilimumab showed a significant decrease in fractional shortening and radial strain with respect to untreated mice, coupled with a significant increase in myocardial expression of NLRP3, MyD88, and several interleukins.

Conclusions: Nivolumab and Ipilimumab exert cytotoxic effects mediated by the NLRP3/IL-1β and MyD88 pathways, leading to pro-inflammatory cytokine storm in heart tissue.
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http://dx.doi.org/10.3390/jpm10040179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711520PMC
October 2020

Inhibiting Monocyte Recruitment to Prevent the Pro-Tumoral Activity of Tumor-Associated Macrophages in Chondrosarcoma.

Cells 2020 04 24;9(4). Epub 2020 Apr 24.

Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', Naples 80131, Italy.

Chondrosarcomas (CHS) are malignant cartilaginous neoplasms with diverse morphological features, characterized by resistance to chemo- and radiation therapies. In this study, we investigated the role of tumor-associated macrophages (TAM)s in tumor tissues from CHS patients by immunohistochemistry. Three-dimensional organotypic co-cultures were set up in order to evaluate the contribution of primary human CHS cells in driving an M2-like phenotype in monocyte-derived primary macrophages, and the capability of macrophages to promote growth and/or invasiveness of CHS cells. Finally, with an in vivo model of primary CHS cells engrafted in nude mice, we tested the ability of a potent peptide inhibitor of cell migration (Ac-d-Tyr-d-Arg-Aib-d-Arg-NH, denoted RI-3) to reduce recruitment and infiltration of monocytes into CHS neoplastic lesions. We found a significant correlation between alternatively activated M2 macrophages and intratumor microvessel density in both conventional and dedifferentiated CHS human tissues, suggesting a link between TAM abundance and vascularization in CHS. In 3D and non-contact cu-culture models, soluble factors produced by CHS induced a M2-like phenotype in macrophages that, in turn, increased motility, invasion and matrix spreading of CHS cells. Finally, we present evidence that RI-3 successfully prevent both recruitment and infiltration of monocytes into CHS tissues, in nude mice.
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http://dx.doi.org/10.3390/cells9041062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226304PMC
April 2020

The effects of the use of platelet-rich plasma gel on local recurrence in an animal model of human fibrosarcoma.

Infect Agent Cancer 2019 28;14:21. Epub 2019 Aug 28.

1Animal Facility, Istituto Nazionale Tumori -IRCCS - Fondazione "G. Pascale", "Fondazione G. Pascale", Via Mariano Semmola, 80131 Naples, Italy.

Background: Platelet-rich-plasma (PRP) is largely used, thanks to its properties, as wound therapy after surgical resection. Several studies and clinical findings have demonstrated that the PRP can accelerate the regeneration and the repair of tissues through the action of the platelet-derived growth factors.

Material And Methods: Our study aimed to investigate the effects of PRP-gel on the rate of tumor relapse by using a mouse model of Human Fibrosarcoma (HF). The radical resection of tumors of mice was conducted under fluorescence-guidance (FGR) by using MacroFluo microscope, after a primary tumor removal with bright-light surgery (BLS).

Results: It was found that the lesion recurrence and the tumor growth were reduced in mice treated with PRP observed in each group of treatment (50%) after 30 days from tumor excision, respect to controls (without statistical significance;  = 0.12). The histopathological and immune-histochemical analysis did not report differences in cellular morphology between the tumors of control and PRP-treated mice.

Conclusion: Our data suggest that PRP-gel, used as an adjuvant treatment for the stimulation of tissue repair and speed up recovery, can impair tumor growth and slow the tumor.
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http://dx.doi.org/10.1186/s13027-019-0237-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712678PMC
August 2019

Naloxone Counteracts the Promoting Tumor Growth Effects Induced by Morphine in an Animal Model of Triple-negative Breast Cancer.

In Vivo 2019 May-Jun;33(3):821-825

S.S.D. Sperimentazione Animale, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy.

Background/aim: Our group has previously demonstrated, in in vitro and in vivo studies on triple-negative breast cancer, that morphine promoted breast cancer progression whereas naloxone was able to reduce it. In this subsequent investigation, we aimed to assess the combinatorial effects of these two drugs in an animal model of triple negative breast cancer.

Materials And Methods: In order to evaluate the in vivo effects of the combination of morphine and naloxone in human breast cancer, a mouse model of human triple-negative breast cancer was generated by injecting the MDA-MB-231 cells subcutaneously in nude mice. Naloxone and morphine were daily intraperitoneally co-injected in mice for 4 weeks at two different doses. Micro-vessel formation was detected by fluorescein isothiocyanate-dextran (100 μl) injected into the lateral tail vein of mice and confirmed by immunohistochemistry for PECAM-1 on mice tumor sections.

Results: In vivo experiments showed that naloxone was able to counteract the promoting effects of morphine on tumor growth. No impairment of micro-vessel formation in tumors of mice treated with the two drugs was observed.

Conclusion: Herein, we demonstrated that naloxone was able to counteract the promoting effects of morphine on tumor growth without impairing micro-vessel formation.
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http://dx.doi.org/10.21873/invivo.11545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559888PMC
August 2019

Development of an anti-BAG3 humanized antibody for treatment of pancreatic cancer.

Mol Oncol 2019 06 17;13(6):1388-1399. Epub 2019 May 17.

BIOUNIVERSA s.r.l., R&D Division, University of Salerno, Baronissi, Italy.

We have previously shown that secreted BAG3 is a potential target for the treatment of pancreatic ductal adenocarcinoma and that pancreatic tumor growth and metastatic dissemination can be reduced by treatment with an anti-BAG3 murine antibody. Here, we used complementarity-determining region (CDR) grafting to generate a humanized version of the anti-BAG3 antibody that may be further developed for possible clinical use. We show that the humanized anti-BAG3 antibody, named BAG3-H2L4, abrogates BAG3 binding to macrophages and subsequent release of IL-6. Furthermore, it specifically localizes into tumor tissues and significantly inhibits the growth of Mia PaCa-2 pancreatic cancer cell xenografts. We propose BAG3-H2L4 antibody as a potential clinical candidate for BAG3-targeted therapy in pancreatic cancer.
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http://dx.doi.org/10.1002/1878-0261.12492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547619PMC
June 2019

Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Oncogene.

Genes (Basel) 2019 02 9;10(2). Epub 2019 Feb 9.

Institute of Experimental Endocrinology and Oncology "G. Salvatore" (IEOS), National Research Council (CNR), 80131 Naples, Italy.

PATZ1 is a transcriptional factor downregulated in thyroid cancer whose re-expression in thyroid cancer cells leads to a partial reversion of the malignant phenotype, including the capacity to proliferate, migrate, and undergo epithelial-to-mesenchymal transition. We have recently shown that is specifically downregulated downstream of the Ras oncogenic signaling through miR-29b, and that restoration of in Ha-Ras transformed FRTL5 rat thyroid cells is able to inhibit their capacities to proliferate and migrate in vitro. Here, we analyzed the impact of expression on the in vivo tumorigenesis of these cells. Surprisingly, FRTL5-Ras-PATZ1 cells showed enhanced tumor initiation when engrafted in nude mice, even if their tumor growth rate was reduced compared to that of FRTL5-Ras control cells. To further investigate the cause of the enhanced tumor engraftment of FRTL5-Ras-PATZ1 cells, we analyzed the stem-like potential of these cells through their capacity to grow as thyrospheres. The results showed that restoration of expression in these cells increases stem cell markers' expression and self-renewal ability of the thyrospheres while limiting their growth capacity. Therefore, we suggest that PATZ1 may play a role in enhancing the stem cell potential of thyroid cancer cells, but, at the same time, it impairs the proliferation of non-stem cells.
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http://dx.doi.org/10.3390/genes10020127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410289PMC
February 2019

Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine.

Onco Targets Ther 2018 19;11:2241-2250. Epub 2018 Apr 19.

Division of Cardiology, Istituto Nazionale Tumori - Irccs Fondazione G. Pascale, Naples, Italy.

Purpose: Pertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody-drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their cardiotoxicity.

Methods: The cardiotoxic effects were tested in vitro on rat cardiomyoblasts, human fetal cardiomyocytes, adult-like cardiomyocytes, and in vivo on a mouse model.

Results: All the treated cardiac cell lines were significantly affected by treatment with the tested drugs. Surprisingly, TDM1 showed stronger inhibitory effects on cardiac cells with respect to trastuzumab and pertuzumab by more significantly reducing the cell viability and by changing the morphology of these cells. TDM1 also affected the beating phenotype of adult-like cardiomyocytes in vitro and reduced fractional shortening and ejection fraction in vivo in a mouse model. We also found that ranolazine attenuated not only the cardiotoxic side effects of trastuzumab but also those of pertuzumab and TDM1, when used in combinatorial treatments both in vitro and in vivo, as demonstrated by the recovery of fractional shortening and ejection fraction values in mice pretreated with TDM1.

Conclusion: We demonstrated that it is possible to predict the eventual cardiotoxic effects of novel approved anticancer drugs early by using in vitro and in vivo approaches, which can also be useful to screen in advance the cardioprotective agents, so as to avoid the onset of unwanted cardiotoxic side effects.
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http://dx.doi.org/10.2147/OTT.S157294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914739PMC
April 2018

Microbiota effects on cancer: from risks to therapies.

Oncotarget 2018 Apr 3;9(25):17915-17927. Epub 2018 Apr 3.

S.S.D Sperimentazione Animale, Istituto Nazionale Tumori, IRCCS, "Fondazione G. Pascale", Naples, Italy.

Gut microbiota, a group of 10 bacteria, eukaryotes and virus living in gastrointestinal tract, is crucial for many physiological processes in particular plays an important role in inflammatory and immune reactions. Several internal and external factors can influence this population, and shifts in their composition, have been demonstrated to contribute and affect different diseases. During dysbiosis several bacteria related to inflammation, one of the most necessary factors in carcinogenesis; it has been shown that some bacterial strains through deregulation of different signals/pathways may affect tumor development through the production of many factors. Gut microbiota might be considered as a holistic hub point for cancer development: direct and indirect involvements have been studying in several neoplasms such as colon rectal cancer, hepatocellular carcinoma and breast cancer. This review discuss over the evidence of crosstalk between gut microbiota and cancer, its ability to modulate chemotherapy, radiotherapy and immunotherapy, and the possibility that the intestinal microbial is a new target for therapeutic approaches to improve the prognosis and quality of life of cancer patients.
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http://dx.doi.org/10.18632/oncotarget.24681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915165PMC
April 2018

Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production.

Front Physiol 2018 6;9:38. Epub 2018 Feb 6.

Division of Cardiology, National Cancer Institute, G. Pascale Foundation, Naples, Italy.

The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for Na inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity.
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http://dx.doi.org/10.3389/fphys.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808165PMC
February 2018

Inhibition of tumor growth by cancer vaccine combined with metronomic chemotherapy and anti-PD-1 in a pre-clinical setting.

Oncotarget 2018 Jan 8;9(3):3576-3589. Epub 2017 Dec 8.

Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Pascale, IRCCS, Naples, Italy.

Tumor microenvironment (TME) is characterized by multiple immune suppressive mechanisms able to suppress anti-tumor effector cell immunity. Combinatorial strategies, including vaccine and immunomodulatory drugs, need to be developed for improved immunotherapy efficacy. A novel combinatorial approach was assessed in C57BL/6 mice injected with mouse melanoma B16F10 cells. A multi-peptide vaccine (PEPT) was combined with a low dose metronomic chemotherapy (MCT) and an anti-PD-1 checkpoint inhibitor (CI). Statistical analysis were performed with the unpaired two-sided Student's -test and ANOVA. Animals treated with the multi-peptide vaccine combined with MCT or CI showed remarkable delay in tumor growth and prolonged survival as compared to control groups. The multi-pronged combination including PEPT+MCT+CI was able to prolong survival in all mice and inhibit tumor growth in 66.6% of mice. All animals which did not show tumor growth were re-challenged with the same melanoma cells and one of them showed complete tumor growth inhibition. The anti-tumor effect was associated with strong T cell immune response to vaccine mutated peptides and significant reduction of regulatory T cells. The combination of a vaccine with MCT and CI was highly efficient in potentiating the vaccine's anti-tumor effects. The approach is highly promising to be moved into clinical trial.
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http://dx.doi.org/10.18632/oncotarget.23181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790484PMC
January 2018

The effects of naloxone on human breast cancer progression: in vitro and in vivo studies on MDA.MB231 cells.

Onco Targets Ther 2018 3;11:185-191. Epub 2018 Jan 3.

Animal Facility Unit, Department of Research, National Cancer Institute "G. Pascale", Naples, Italy.

Background: Naloxone is viewed as a specific competitive opioid antagonist acting at the level of opioid receptors (μ, δ, and κ) with blended agonist-adversary or agonist action. The role of naloxone in tumor cell growth has been poorly studied in human cancer cell lines.

Materials And Methods: In the present study, we report findings from in vitro and in vivo experiments performed to evaluate the effects of naloxone on human breast cancer cell growth and progression. In vitro assays were conducted on estrogen receptor-negative human breast carcinoma cells, MDA.MB231, treated with naloxone at different concentrations (10-100 μM). In vivo experiments were performed on a mouse model of human triple-negative breast cancer generated by using MDA.MB231 injected subcutaneously in mice. Naloxone was daily intraperitoneally injected in mice at 0.357 mg/kg for 2 weeks and at 0.714 mg/kg for the next 2 weeks. Microvessels formation was detected by fluorescein isothiocyanate-dextran (100 μL) injected into the tail vein of mice and confirmed by immunohistochemistry with CD31 on mice tumor sections.

Results: In vitro tests showed that the cell proliferation of MDA.MB231 was inhibited by naloxone in a dose-dependent manner, whereas the cell death was increased. In vivo studies demonstrated that tumors of mice treated with naloxone were significantly smaller than those observed in the control groups, as long as naloxone was administered. Finally, naloxone was not able to impair the microvessel formation in tumors of treated mice.

Conclusion: Our data showed, for the first time, that naloxone reduced breast cancer progression without affecting angiogenesis.
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http://dx.doi.org/10.2147/OTT.S145780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757202PMC
January 2018

HMGA2 cooperates with either p27 deficiency or Cdk4 mutation in pituitary tumorigenesis.

Cell Cycle 2018 30;17(5):580-588. Epub 2018 Jan 30.

a CNR - Institute of Experimental Endocrinology and Oncology - c/o Department of Molecular Medicine and Medical Biotechnologies , University of Naples "Federico II" , Naples , Italy.

We have previously reported a critical role of HMGA proteins in pituitary tumorigenesis since either the Hmga1 or Hmga2 gene overexpression/activation induces the development of mixed growth hormone/prolactin cell pituitary adenomas by activating the E2F transcription factor 1, and then enhancing the G1/S transition of the cell cycle. Consistently, amplification and overexpression of the HMGA2 gene was found in human pituitary prolactinomas. Since impairment of the cell cycle control represents a feature of experimental and human pituitary adenomas, we have investigated the possible synergism between the alterations of other cell cycle regulators, such as p27 deficiency or Cdk4 mutation, with Hmga2 overexpression in pituitary tumorigenesis. Therefore, we crossed the Hmga2/T mice, overexpressing the truncated/active form of the Hmga2 gene, either with the knockout mice for p27, or with the knockin mice for the Cdk4 mutation, both developing pituitary adenomas. Increased incidence and decreased latency in the development of pituitary lesions appeared in double mutant Hmga2/T;Cdk4 mice, and increased features of invasiveness and atypia were observed in pituitary tumors of both Hmga2/T;p27-ko and Hmga2/T;Cdk4 double mutant mice as compared with single mutant compounds. Interestingly, most of these mice develop pituitary adenomas with high Ki67 index, extrasellar expansion and brain tissue infiltration, representing good mouse models for human aggressive pituitary adenomas. Taken together, the results reported here indicate a cooperation between HMGA2 overexpression and either p27 or CDK4 impairment in promoting pituitary tumor development and progression.
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http://dx.doi.org/10.1080/15384101.2017.1403682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969540PMC
September 2019

Role of Nigella sativa and Its Constituent Thymoquinone on Chemotherapy-Induced Nephrotoxicity: Evidences from Experimental Animal Studies.

Nutrients 2017 Jun 17;9(6). Epub 2017 Jun 17.

Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-"Fondazione G. Pascale", Via Mariano Semmola, 80131 Naples, Italy.

Background: Most chemotherapeutic drugs are known to cause nephrotoxicity. Therefore, new strategies have been considered to prevent chemotherapy-induced nephrotoxicity. It is of note that (NS), or its isolated compound Thymoquinone (TQ), has a potential role in combating chemotherapy-induced nephrotoxicity.

Aim: To analyze and report the outcome of experimental animal studies on the protective effects of NS/TQ on chemotherapy-associated kidney complications.

Design: Standard systematic review and narrative synthesis.

Data Sources: MEDLINE, EMBASE databases were searched for relevant articles published up to March 2017. Additionally, a manual search was performed. Criteria for a study's inclusion were: conducted in animals, systematic reviews and meta-analysis, containing data on nephroprotective effects of NS/TQ compared to a placebo or other substance. All strains and genders were included.

Results: The database search yielded 71 studies, of which 12 (cisplatin-induced nephrotoxicity 8; methotrexate-induced nephrotoxicity 1; doxorubicin-induced nephrotoxicity 2; ifosfamide-induced nephrotoxicity 1) were included in this review.

Conclusions: Experimental animal studies showed the protective effect of NS, or TQ, on chemotherapy-induced nephrotoxicity. These effects are caused by decreasing lipid peroxidation and increasing activity of antioxidant enzymes in renal tissue of chemotherapy-treated animals.
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http://dx.doi.org/10.3390/nu9060625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490604PMC
June 2017

Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas.

Sci Rep 2017 05 2;7(1):1312. Epub 2017 May 2.

Peptipharma, Viale Città D'Europa 679, 00144, Rome, Italy.

The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide Receptors (FPRs). Since both uPAR and FPR1 are involved in tumor progression, the uPAR-FPR1 interaction is an attractive therapeutic target. We previously described peptide antagonists of the uPAR-FPR1 interaction that inhibited cell migration and angiogenesis. To develop enzyme-resistant analogues, we applied here the Retro-Inverso (RI) approach, whereby the topology of the side chains is maintained by inverting the sequence of the peptide and the chirality of all residues. Molecular dynamics suggests that peptide RI-3 adopts the turn structure typical of uPAR-FPR1 antagonists. Accordingly, RI-3 is a nanomolar competitor of N-formyl-Met-Leu-Phe for binding to FPR1 and inhibits migration, invasion, trans-endothelial migration of sarcoma cells and VEGF-triggered endothelial tube formation. When sarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density, circulating tumor cells and pulmonary metastases were significantly reduced in animals treated daily with 6 mg/Kg RI-3 as compared to animals treated with vehicle only. Thus, RI-3 represents a promising lead for anti-metastatic drugs.
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http://dx.doi.org/10.1038/s41598-017-01425-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430962PMC
May 2017

Tumour biomarkers: homeostasis as a novel prognostic indicator.

Open Biol 2016 12;6(12)

Struttura Semplice Dipartimentale Sperimentazione Animale, Istituto Nazionale Tumori 'Fondazione G. Pascale', IRCCS, Via Mariano Semmola, 80131 Naples, Italy

The term 'personalized medicine' refers to a medical procedure that consists in the grouping of patients based on their predicted individual response to therapy or risk of disease. In oncologic patients, a 'tailored' therapeutic approach may potentially improve their survival and well-being by not only reducing the tumour, but also enhancing therapeutic response and minimizing the adverse effects. Diagnostic tests are often used to select appropriate and optimal therapies that rely both on patient genome and other molecular/cellular analysis. Several studies have shown that lifestyle and environmental factors can influence the epigenome and that epigenetic events may be involved in carcinogenesis. Thus, in addition to traditional biomarkers, epigenetic factors are raising considerable interest, because they could potentially be used as an excellent tool for cancer diagnosis and prognosis. In this review, we summarize the role of conventional cancer genetic biomarkers and their association with epigenomics. Furthermore, we will focus on the so-called 'homeostatic biomarkers' that result from the physiological response to cancer, emphasizing the concept that an altered 'new' homeostasis influence not only tumour environment, but also the whole organism.
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http://dx.doi.org/10.1098/rsob.160254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204124PMC
December 2016

Antineoplastic-related cardiotoxicity, morphofunctional aspects in a murine model: contribution of the new tool 2D-speckle tracking.

Onco Targets Ther 2016 2;9:6785-6794. Epub 2016 Nov 2.

Division of Cardiology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy.

Objective: Considering that global left ventricular systolic radial strain is a sensitive technique for the early detection of left ventricular dysfunction due to antineoplastics and the analysis of segmental myocardial contractility, we evaluated this technique for early detection of trastuzumab-related cardiotoxicity by comparing it with cardiac structural damage.

Methods: Groups of six mice were injected with trastuzumab or doxorubicin, used either as single agents or in combination. Cardiac function was evaluated by transthoracic echocardiography measurements before and after treatment for 2 or 7 days, by using a Vevo 2100 high-resolution imaging system. After echocardiography, mice were euthanized, and hearts were processed for histological evaluations, such as cardiac fibrosis, apoptosis, capillary density, and inflammatory response.

Results: Trastuzumab-related cardiotoxicity was detected early by 2D strain imaging. Radial strain was reduced after 2 days in mice treated with trastuzumab alone (21.2%±8.0% vs 40.5%±4.8% sham; <0.01). Similarly, trastuzumab was found to induce apoptosis, capillary density reduction, and inflammatory response in cardiac tissue after 2 days of treatment, in a fashion similar to doxorubicin. On the contrary, fractional shortening reduction and cardiac fibrosis were observed only after 7 days of trastuzumab treatment, in contrast to doxorubicin treatment which induced early fibrosis and fractional shortening reduction.

Conclusion: The reduction of left ventricular systolic strain after 2 days of trastuzumab treatment may indicate early myocardial functional damage before the reduction in left ventricular ejection fraction and this early dysfunction is well correlated with structural myocardial damage, such as apoptosis and inflammatory response. Fractional shortening reduction after 7 days of trastuzumab treatment is related to fibrosis in cardiac tissue.
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http://dx.doi.org/10.2147/OTT.S106528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098586PMC
November 2016

The urokinase receptor-derived cyclic peptide [SRSRY] suppresses neovascularization and intravasation of osteosarcoma and chondrosarcoma cells.

Oncotarget 2016 Aug;7(34):54474-54487

Neoplastic Progression Unit, Department of Experimental Oncology, IRCCS Istituto Nazionale Tumori "Fondazione G. Pascale", Naples, Italy.

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility and angiogenesis by interacting with the formyl peptide receptor type 1 (FPR1). In this study, we present evidence that the cyclization of the uPAR88-92 sequence generates a new potent inhibitor of migration, and extracellular matrix invasion of human osteosarcoma and chondrosarcoma cells expressing comparable levels of FPR1 on cell surface. In vitro, the cyclized peptide [SRSRY] prevents formation of capillary-like tubes by endothelial cells co-cultured with chondrosarcoma cells and trans-endothelial migration of osteosarcoma and chondrosarcoma cells. When chondrosarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density and circulating tumor cells in blood samples collected before the sacrifice, were significantly reduced in animals treated daily with i.p-administration of 6 mg/Kg [SRSRY] as compared to animals treated with vehicle only. Our findings indicate that [SRSRY] prevents three key events occurring during the metastatic process of osteosarcoma and chondrosarcoma cells: the extracellular matrix invasion, the formation of a capillary network and the entry into bloodstream.
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http://dx.doi.org/10.18632/oncotarget.9976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342356PMC
August 2016

Mouse Models in Prostate Cancer Translational Research: From Xenograft to PDX.

Biomed Res Int 2016 18;2016:9750795. Epub 2016 May 18.

Animal Facility Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", IRCCS, 80131 Naples, Italy.

Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery.
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http://dx.doi.org/10.1155/2016/9750795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887629PMC
January 2017

PATZ1 is a target of miR-29b that is induced by Ha-Ras oncogene in rat thyroid cells.

Sci Rep 2016 04 29;6:25268. Epub 2016 Apr 29.

Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), 80131 Naples, Italy.

The regulatory transcriptional factor PATZ1 is constantly downregulated in human thyroid cancer where it acts as a tumour suppressor by targeting p53-dependent genes involved in Epithelial-Mesenchymal Transition and cell migration. The aim of the present work was to elucidate the upstream signalling mechanisms regulating PATZ1 expression in thyroid cancer cells. The bioinformatics search for microRNAs able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-29b since it was found upregulated in rat thyroid differentiated cells transformed by the Ha-Ras oncogene towards a high proliferating and high migratory phenotype resembling that of anaplastic carcinomas. Functional assays confirmed PATZ1 as a target of miR-29b, and, consistently, an inverse correlation between miR-29b and PATZ1 protein levels was found upon induction of Ha-Ras oncogene expression in these cells. Interestingly, restoration of PATZ1 expression in rat thyroid cells stably expressing the Ha-Ras oncogene decreased cell proliferation and migration, indicating a key role of PATZ1 in Ras-driven thyroid transformation. Together, these results suggest a novel mechanism regulating PATZ1 expression based on the upregulation of miR-29b expression induced by Ras oncogene.
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http://dx.doi.org/10.1038/srep25268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850481PMC
April 2016

Strain Analysis in the Assessment of a Mouse Model of Cardiotoxicity due to Chemotherapy: Sample for Preclinical Research.

In Vivo 2016 May-Jun;30(3):279-90

Cardiology Unit, "G. Pascale Foundation", IRCCS, Naples, Italy.

Background: In recent years, the development of more effective anticancer drugs has provided great benefits in patients' quality of life by improving both prognosis and disease-free survival. Nevertheless, the frequency and severity of side-effects, with particular reference to cardiac toxicity, have gained particular attention. The purpose of this study was to create a precise and sensitive preclinical model, able to identify early contractile dysfunction in mice treated with chemotherapy, through use of speckle-tracking echocardiography.

Materials And Methods: We generated a mouse model of cardiotoxicity induced by doxorubicin. C57BL 6 mice were divided into two groups, treated for 7 days by intraperitoneal injections of placebo (vehicle) or doxorubicin (2.17 mg/kg), in order to characterize the cardiac phenotype in vivo.

Results: We demonstrated that doxorubicin caused ealy remodeling of the left ventricle: after two days of therapy, the radial, circumferential and strain rates were reduced respectively by 35%, 34%, and 39% (p-value ≤0.001). Moreover, histological analysis revealed that doxorubicin treatment increased fibrosis, cardiomyocyte diameter and apoptosis.

Conclusion: In a murine model of doxorubicin-induced cardiac injury, we detected left ventricular dysfunction followed by alterations in conventional echocardiographic indices. Our study suggests that a change in strain could be an effective early marker of myocardial dysfunction for new anticancer treatments and, in preclinical studies, it might also be a valuable indicator for the assessment of activity of cardioprotective agents.
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March 2017

A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice.

J Transl Med 2016 Feb 24;14:58. Epub 2016 Feb 24.

Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy.

Background: The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.

Methods: In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious.

Results: Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA.

Conclusion: The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.
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http://dx.doi.org/10.1186/s12967-016-0812-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766679PMC
February 2016

BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages.

Nat Commun 2015 Nov 2;6:8695. Epub 2015 Nov 2.

Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno 84081, Italy.

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.
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http://dx.doi.org/10.1038/ncomms9695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659838PMC
November 2015

Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice.

Sci Rep 2015 Sep 7;5:13864. Epub 2015 Sep 7.

Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Viale Europa, 88100, Catanzaro, Italy.

Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4(+) and CD8(+) T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation.
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http://dx.doi.org/10.1038/srep13864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561375PMC
September 2015

Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression.

Biomed Res Int 2015 3;2015:161508. Epub 2015 May 3.

Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", IRCCS, Via Mariano Semmola, 80131 Naples, Italy.

Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.
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http://dx.doi.org/10.1155/2015/161508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433634PMC
March 2016

The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo.

Int J Oncol 2015 Aug 8;47(2):527-34. Epub 2015 Jun 8.

Animal Facility Unit, National Institute of Tumours of Naples 'Pascale', Naples, Italy.

The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through β-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development in vitro and in vivo. Treatments with norepinephrine (β2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (β-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that β2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing β2AR.
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http://dx.doi.org/10.3892/ijo.2015.3038DOI Listing
August 2015

Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity.

Oncotarget 2015 Jun;6(17):15628-38

Istituto per l'Endocrinologia ed Oncologia Sperimentale del CNR e/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

CCDC6 was originally identified upon rearrangement with RET in human thyroid papillary carcinomas generating the RET/PTC1 oncogene. We have previously reported that CCDC6 interacts with CREB1 and represses its transcriptional activity. Since the function of at least one allele of CCDC6 is lost following RET/PTC1 rearrangements, we aimed at the generation of mice, carrying a CCDC6 mutant gene. Previous studies suggested that the coiled-coil domain of CCDC6, mainly encoded by human exon 2, is required for the protein function. Therefore, we engineered a murine Ccdc6 construct, carrying a deletion of the exon 2, that was able to exert only a mild repression on CREB1 transcriptional activity, with respect to the wild type Ccdc6. Subsequently, we generated Ccdc6-ex2 knock-in mice. These mice developed thyroid hyperplasia associated with an enhanced CREB1 activity and an increased expression of the CREB-1 regulated genes. These results strongly support a CCDC6 promoting role, ascribed to its functional impairment, in the development of thyroid papillary carcinomas harboring the RET/PTC1 oncogene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558175PMC
http://dx.doi.org/10.18632/oncotarget.3858DOI Listing
June 2015

Dissecting the role of curcumin in tumour growth and angiogenesis in mouse model of human breast cancer.

Biomed Res Int 2015 23;2015:878134. Epub 2015 Mar 23.

Hepatobiliary Unit, Istituto Nazionale per la Studio e la Cura dei Tumori "Fondazione G. Pascale" (IRCCS), Via Mariano Semmola, 80131 Naples, Italy.

Breast cancer is considered the most common cancer for women worldwide and it is now the second leading cause of cancer-related deaths among females in the world. Since breast cancer is highly resistant to chemotherapy, alternative anticancer strategies have been developed. In particular, many studies have demonstrated that curcumin, a derivative of turmeric, can be used as natural agent in treatment of some types of cancer by playing antiproliferative and antioxidant effects. In our study, we assessed the antitumor activities of curcumin in ER-negative human breast cancer cell line resistant to chemotherapy, MDA.MB231 by in vitro and in vivo experiments. In vitro data allowed us to demonstrate that curcumin played a role in regulation of proliferation and apoptosis in MDA.MB231 cells. In vivo, by generation of mouse model of breast cancer, we showed that treatment of curcumin inhibited tumor growth and angiogenesis. Specifically, we showed that curcumin is able to deregulate the expression of cyclin D1, PECAM-1, and p65, which are regulated by NF-κB. Our data demonstrated that curcumin could be used as an adjuvant agent to chemotherapy in treatment of triple negative breast cancer.
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http://dx.doi.org/10.1155/2015/878134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386568PMC
December 2015

PATZ1 acts as a tumor suppressor in thyroid cancer via targeting p53-dependent genes involved in EMT and cell migration.

Oncotarget 2015 Mar;6(7):5310-23

Institute of Experimental Endocrinology and Oncology (IEOS), National Research Counsil (CNR), 80131 Naples, Italy.

PATZ1, a POZ-Zinc finger protein, is emerging as an important regulator of development and cancer, but its cancer-related function as oncogene or tumor-suppressor is still debated. Here, we investigated its possible role in thyroid carcinogenesis. We demonstrated PATZ1 is down-regulated in thyroid carcinomas compared to normal thyroid tissues, with an inverse correlation to the degree of cell differentiation. In fact, PATZ1 expression was significantly further down-regulated in poorly differentiated and anaplastic thyroid cancers compared to the papillary histotype, and it resulted increasingly delocalized from the nucleus to the cytoplasm proceeding from differentiated to undifferentiated thyroid carcinomas. Restoration of PATZ1 expression in three thyroid cancer-derived cell lines, all characterized by fully dedifferentiated cells, significantly inhibited their malignant behaviors, including in vitro proliferation, anchorage-independent growth, migration and invasion, as well as in vivo tumor growth. Consistent with recent studies showing a role for PATZ1 in the p53 pathway, we showed that ectopic expression of PATZ1 in thyroid cancer cells activates p53-dependent pathways opposing epithelial-mesenchymal transition and cell migration to prevent invasiveness. These results provide insights into a potential tumor-suppressor role of PATZ1 in thyroid cancer progression, and thus may have potential clinical relevance for the prognosis and therapy of thyroid cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467151PMC
http://dx.doi.org/10.18632/oncotarget.2776DOI Listing
March 2015
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