V. Ciaramella
University of Naples Federico II
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Publication
Featured researches published by V. Ciaramella.
Oncotarget | 2016
Carminia Maria Della Corte; V. Ciaramella; Concetta Di Mauro; Maria Domenica Castellone; Federica Papaccio; Morena Fasano; Ferdinando Carlo Sasso; Erika Martinelli; Teresa Troiani; Ferdinando De Vita; Michele Orditura; Roberto Bianco; Fortunato Ciardiello; Floriana Morgillo
Purpose Metformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization. Experimental design Since single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene. Results The combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters. Conclusions Metformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9.
Oncotarget | 2017
Carminia Maria Della Corte; Umberto Malapelle; Elena Vigliar; Francesco Pepe; Giancarlo Troncone; V. Ciaramella; Teresa Troiani; Erika Martinelli; Valentina Belli; Fortunato Ciardiello; Floriana Morgillo
Purpose The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors. Experimental design We developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib). Results HCC827-derived xenografts and with acquired resistance to EGFR-inhibitors were sensitive to the sequential use of first-, second- and third-generation EGFR-TKIs. Continuous EGFR inhibition of first-generation resistant tumors by sequential treatment with afatinib plus/minus cetuximab, followed by osimertinib, represented an effective therapeutic strategy in this model. Whereas T790M resistance mutation was not detected, a major mechanism of acquired resistance was the activation of components of the Hedgehog (Hh) pathway. This phenomenon was accompanied by epithelial-to-mesenchymal transition. Cell lines established in vitro from gefitinib-, or afatinib- or osimertinib-resistant tumors showed metastatic properties and maintained EGFR-TKIs resistance in vitro, that was reverted by the combined blockade of Hh, with the selective SMO inhibitor sonidegib, and EGFR. Conclusions EGFR-mutant NSCLC can benefit from continuous treatment with EGFR-inhibitors, indepenently from mechanisms of resistance. In a complex and heterogenous scenario, Hh showed an important role in mediating resistance to EGFR-inhibitors through the induction of mesenchymal properties.
Oncotarget | 2017
Floriana Morgillo; Carminia Maria Della Corte; Anna Diana; Concetta Di Mauro; V. Ciaramella; Giusi Barra; Valentina Belli; Elisena Franzese; Roberto Bianco; Evaristo Maiello; Ferdinando De Vita; Fortunato Ciardiello; M. Orditura
Purpose The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Kα selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy. Experimental design The efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence. Results A significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination. Conclusions Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.
Journal of Medicinal Chemistry | 2017
Floriana Morgillo; Giorgio Amendola; Carminia Maria Della Corte; Chiara Giacomelli; Lorenzo Botta; Salvatore Di Maro; Anna Messere; V. Ciaramella; Sabrina Taliani; Luciana Marinelli; Maria Letizia Trincavelli; Claudia Martini; Ettore Novellino; Fortunato Ciardiello; Sandro Cosconati
The Breast | 2018
M. Orditura; C.M. Della Corte; A. Diana; V. Ciaramella; Elisena Franzese; V. Famiglietti; Iacopo Panarese; Renato Franco; A. Grimaldi; Angela Lombardi; Michele Caraglia; A. Santoriello; Eugenio Procaccini; Eva Lieto; Evaristo Maiello; F. De Vita; Fortunato Ciardiello; Floriana Morgillo
Annals of Oncology | 2018
C M Della Corte; Giusi Barra; V. Ciaramella; R. Di Liello; Morena Fasano; F. Ciardiello; Floriana Morgillo
Annals of Oncology | 2018
V. Ciaramella; C.M. Della Corte; Giusi Barra; R. Di Liello; G. Viscardi; M. Orditura; Erika Martinelli; F. Ciardiello; Floriana Morgillo
Annals of Oncology | 2018
R. Di Liello; G. Viscardi; V. Ciaramella; Giusi Barra; Grazia Esposito; Morena Fasano; F. Ciardiello; Floriana Morgillo
Annals of Oncology | 2017
G. Viscardi; V. Ciaramella; C.M. Della Corte; F. Papaccio; G. Esposito; R. Di Liello; Teresa Troiani; M. Orditura; F. Ciardiello; Floriana Morgillo
Annals of Oncology | 2017
A. Diana; Floriana Morgillo; C.M. Della Corte; C. Di Mauro; V. Ciaramella; Giusi Barra; Valentina Belli; Elisena Franzese; R. Bianco; Evaristo Maiello; F. De Vita; F. Ciardiello; M. Orditura