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Pancreatic Neoplasms: HELP
Articles by Carlotta Granchi
Based on 3 articles published since 2010
(Why 3 articles?)
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Between 2010 and 2020, C. Granchi wrote the following 3 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article First Examples of H 2019

Fortunato, Serena / Lenzi, Chiara / Granchi, Carlotta / Citi, Valentina / Martelli, Alma / Calderone, Vincenzo / Di Pietro, Sebastiano / Signore, Giovanni / Di Bussolo, Valeria / Minutolo, Filippo. ·Dipartimento di Farmacia , Università di Pisa , Via Bonanno Pisano , 56126 Pisa , Italy. · NEST, Scuola Normale Superiore and NANO-CNR , Piazza San Silvestro 12 , 56127 Pisa , Italy. · Dipartimento di Chimica e Chimica Industriale , Università di Pisa , Via G. Moruzzi 13 , 56124 Pisa , Italy. ·Bioconjug Chem · Pubmed #30609890.

ABSTRACT: H

2 Article Phospho-Akt overexpression is prognostic and can be used to tailor the synergistic interaction of Akt inhibitors with gemcitabine in pancreatic cancer. 2017

Massihnia, Daniela / Avan, Amir / Funel, Niccola / Maftouh, Mina / van Krieken, Anne / Granchi, Carlotta / Raktoe, Rajiv / Boggi, Ugo / Aicher, Babette / Minutolo, Filippo / Russo, Antonio / Leon, Leticia G / Peters, Godefridus J / Giovannetti, Elisa. ·Department of Medical Oncology VU University Medical Center, Cancer Center Amsterdam, CCA room 1.52, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. · Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy. · Metabolic syndrome Research center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. · Cancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy. · Department of Pharmacy, University of Pisa, Pisa, Italy. · Department of Surgery, University of Pisa, Pisa, Italy. · Æterna Zentaris GmbH, Frankfurt am Main, Frankfurt, Germany. · Department of Medical Oncology VU University Medical Center, Cancer Center Amsterdam, CCA room 1.52, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. e.giovannetti@vumc.nl. · Cancer Pharmacology Lab, AIRC Start Up Unit, University of Pisa, Pisa, Italy. e.giovannetti@vumc.nl. ·J Hematol Oncol · Pubmed #28061880.

ABSTRACT: BACKGROUND: There is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine. METHODS: Phospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients (n = 100). Data were analyzed by Fisher and log-rank test. In vitro studies were performed in 14 PDAC cells, including seven primary cultures, characterized for their Akt1 mRNA and phospho-Akt/Akt levels by quantitative-RT-PCR and immunocytochemistry. Growth inhibitory effects of Akt inhibitors and gemcitabine were evaluated by SRB assay, whereas modulation of Akt and phospho-Akt was investigated by Western blotting and ELISA. Cell cycle perturbation, apoptosis-induction, and anti-migratory behaviors were studied by flow cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method. RESULTS: Immunohistochemistry of TMAs revealed a correlation between phospho-Akt expression and worse outcome, particularly in patients with the highest phospho-Akt levels, who had significantly shorter overall and progression-free-survival. Similar expression levels were detected in LPC028 primary cells, while LPC006 were characterized by low phospho-Akt. Remarkably, Akt inhibitors reduced cancer cell growth in monolayers and spheroids and synergistically enhanced the antiproliferative activity of gemcitabine in LPC028, while this combination was antagonistic in LPC006 cells. The synergistic effect was paralleled by a reduced expression of ribonucleotide reductase, potentially facilitating gemcitabine cytotoxicity. Inhibition of Akt decreased cell migration and invasion, which was additionally reduced by the combination with gemcitabine. This combination significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028, but not in LPC006 cells. However, targeting the key glucose transporter Glut1 resulted in similar apoptosis induction in LPC006 cells. CONCLUSIONS: These data support the analysis of phospho-Akt expression as both a prognostic and a predictive biomarker, for the rational development of new combination therapies targeting the Akt pathway in PDAC. Finally, inhibition of Glut1 might overcome resistance to these therapies and warrants further studies.

3 Article Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. 2014

Maftouh, M / Avan, A / Sciarrillo, R / Granchi, C / Leon, L G / Rani, R / Funel, N / Smid, K / Honeywell, R / Boggi, U / Minutolo, F / Peters, G J / Giovannetti, E. ·Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV, Amsterdam, Netherlands. · Department of Pharmacy, University of Pisa, Pisa, Italy. · Center for Biomedical Research of the Canary Islands, Instituto de Tecnologias Biomedicas, University of La Laguna, La Laguna, Spain. · Department of Surgery, University of Pisa, Pisa, Italy. ·Br J Cancer · Pubmed #24178759.

ABSTRACT: BACKGROUND: Hypoxia is a driving force in pancreatic-ductal-adenocarcinoma (PDAC) growth, metastasis and chemoresistance. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis, ensuring supply of energy and anabolites in hypoxic-environments. Therefore, we investigated the molecular mechanisms underlying the pharmacological interaction of novel LDH-A inhibitors in combination with gemcitabine in PDAC cells. METHODS: Lactate dehydrogenase A levels were studied by quantitative RT-PCR, western blot, immunofluorescence and activity assays in 14 PDAC cells, including primary-cell-cultures and spheroids, in normoxic and hypoxic conditions. Cell proliferation, migration and key determinants of drug activity were evaluated by sulforhodamine-B-assay, wound-healing assay, PCR and LC-MS/MS. RESULTS: Lactate dehydrogenase A was significantly increased under hypoxic conditions (1% O2), where the novel LDH-A inhibitors proved to be particularly effective (e.g., with IC50 values of 0.9 vs 16.3 μM for NHI-1 in LPC006 in hypoxia vs normoxia, respectively). These compounds induced apoptosis, affected invasiveness and spheroid-growth, reducing expression of metalloproteinases and cancer-stem-like-cells markers (CD133+). Their synergistic interaction with gemcitabine, with combination index values <0.4 in hypoxia, might also be attributed to modulation of gemcitabine metabolism, overcoming the reduced synthesis of phosphorylated metabolites. CONCLUSION: Lactate dehydrogenase A is a viable target in PDAC, and novel LDH-A inhibitors display synergistic cytotoxic activity with gemcitabine, offering an innovative tool in hypoxic tumours.