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4 results on '"Tamburrino, Anna"'

1. Rationale and clinical use of multitargeting anticancer agents.

Author

Melisi D, Piro G, Tamburrino A, Carbone C, and Tortora G

Subjects
Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use
Abstract

Human solid tumors contain genetically distinct subpopulations of tumor cells that can be enriched under selective pressure of specific treatments. This heterogeneous nature reflects the dynamism of drug response and it represents a fundamental driver of resistance. Moreover, the complexity of cancer disease is increased by the activity of cross-talking, redundant signaling pathways, escape pathways and compensatory events, which triggers activation of secondary growth and survival. Broad multi-targeted approaches are requested to overcome a complex, heterogeneous, and dynamic disease such as cancer., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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2. Insights into the molecular function of the inactivating mutations of B-Raf involving the DFG motif.

Author

Moretti S, De Falco V, Tamburrino A, Barbi F, Tavano M, Avenia N, Santeusanio F, Santoro M, Macchiarulo A, and Puxeddu E

Subjects
Amino Acid Motifs genetics, Amino Acid Substitution, Animals, COS Cells, Chlorocebus aethiops, Humans, Mice, NIH 3T3 Cells, Neoplasms genetics, Protein Structure, Quaternary genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-raf genetics, Proto-Oncogene Proteins c-raf metabolism, Mutation, Missense, Neoplasms metabolism, Proto-Oncogene Proteins B-raf metabolism
Abstract

BRAF gene mutations have been associated with human cancers. Among the naturally occurring mutations, two that involve amino acids of the conserved DFG motif in the activation loop (D594V and G596R), appear to be inactivating. Aim of this study was to analyze the molecular mechanisms involved in the loss of function of B-Raf inactivating mutation G596R. Furthermore, the ability of the B-Raf DFG motif mutants to generate heterodimers with C-Raf and the possible functional consequences of the B-Raf/C-Raf heterodimer formation was examined. Wet molecular experiments in HEK293T cells demonstrate that B-Raf(G596R) is a kinase-impaired mutant. Molecular dynamics simulations show that the loss of function of B-Raf(G596R) depends on a restraining effect of Arg596 on the catalytic residue Asp594, which results in the loss of the appropriate spatial localization and/or conformation of the latter necessary for anchoring ATP to the enzyme. Exploration of B-Raf/C-Raf heterodimer formation indicates the occurrence of functioning heterodimers in the case of all the DFG B-Raf mutants, independently from the expected differences in spatial conformation of the activation loop, although the transforming activity of the mutants appear negligible. In conclusion, this study delivers novel information on the functional properties of the B-Raf DFG motif inactivating mutants and on the mechanisms driving B-Raf/C-Raf heterodimerization and consequent C-Raf transactivation.

Published
2009
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3. The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells

Author

Fortunato Ciardiello, Gennaro Chiappetta, Massimo Santoro, Giancarlo Troncone, Giampaolo Tortora, James A. Fagin, Valentina De Falco, Donata Vitagliano, Francesca Carlomagno, Anderson J. Ryan, Sabrina Coluzzi, Anna Tamburrino, Vitagliano, Donata, De Falco, V., Tamburrino, Anna, Coluzzi, S., Troncone, Giancarlo, Chiappetta, G., Ciardiello, F, Tortora, G., Fagin, J., Ryan, A. J., Carlomagno, Francesca, Santoro, Massimo, Vitagliano, D, DE FALCO, V, Tamburrino, A, Coluzzi, S, Troncone, G, Chiappetta, G, Ciardiello, Fortunato, Tortora, G, Fagin, Ja, Ryan, Aj, Carlomagno, F, and Santoro, M.

Subjects
MAPK/ERK pathway, Cancer Research, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system, endocrine system diseases, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Vandetanib, Tyrosine-kinase inhibitor, Endocrinology, Piperidines, Cell Line, Tumor, tyrosine kinase inhibitors, medicine, thyroid cancer, Humans, Thyroid Neoplasms, Epidermal growth factor receptor, Protein kinase A, Protein Kinase Inhibitors, neoplasms, Cell Proliferation, ret, medullary thyroid carcinoma, tyrosine kinase inhibitor, biology, Kinase, Cell growth, Proto-Oncogene Proteins c-ret, tyrosine kinase, Transforming Growth Factor alpha, targeted therapy, Vascular Endothelial Growth Factor Receptor-2, ErbB Receptors, Oncology, Carcinoma, Medullary, Mutation, Quinazolines, Cancer research, biology.protein, cancer therapy, Tyrosine kinase, carcinoma midollare della tiroide, Signal Transduction, medicine.drug
Abstract

Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.

Published
2011

4. Cytostatic Activity of Adenosine Triphosphate-Competitive Kinase Inhibitors in BRAF Mutant Thyroid Carcinoma Cells

Author

Anna Tamburrino, Rebecca E. Schweppe, Giuliana Salvatore, Massimo Santoro, Paolo Salerno, Tito Claudio Nappi, Valentina De Falco, Gideon Bollag, Giancarlo Vecchio, Salerno, P, DE FALCO, Valentina, Tamburrino, Anna, Nappi, Tc, Vecchio, Giancarlo, Schweppe, Re, Bollag, G, Santoro, Massimo, and Salvatore, G.

Subjects
Serum, Indoles, genetic structures, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Drug Evaluation, Preclinical, medicine.disease_cause, Biochemistry, thyroid, Adenosine Triphosphate, Endocrinology, Tumor Cells, Cultured, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, Vemurafenib, Thyroid cancer, Sulfonamides, Kinase, Thyroid, General Medicine, Editorial, medicine.anatomical_structure, KRAS, medicine.drug, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, kinase, Biology, Binding, Competitive, BRAF, Thyroid carcinoma, Translational Highlights from Jcem, Internal medicine, medicine, Humans, Thyroid Neoplasms, HRAS, Protein Kinase Inhibitors, neoplasms, Molecular Biology, Cell Proliferation, therapy, Carcinoma, Biochemistry (medical), Cytostatic Agents, medicine.disease, digestive system diseases, Cancer research, Mutant Proteins, V600E
Abstract

Context: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations. Objective: The aim was to study the effects of the two BRAF V600E ATP-competitive kinase inhibitors, PLX4032 and PLX4720, in thyroid carcinoma cell lines. Experimental Design: We examined the activity of PLX4032 and PLX4720 in thyroid carcinoma cell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control. Results: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC50) ranging from 78-113 nM for PLX4720 and from 29-97 nM for PLX4032. Doses equal to or higher than 500 nM were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK 1/2 and MAPK kinase (MEK) 1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G1 block and altered expression of genes involved in the control of G1-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in control mice. This inhibition was associated with reduction of phospho-ERK and phospho-MEK levels. Conclusions: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.

Published
2010

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