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D'Alessio A.,Cell Biology and Biotherapy Unit | De Luca A.,Cell Biology and Biotherapy Unit | Maiello M.R.,Cell Biology and Biotherapy Unit | Lamura L.,Cell Biology and Biotherapy Unit | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2010

Treatment of breast cancer cells with a combination of the EGFR-tyrosine kinase inhibitor (EGFR-TKI) gefitinib and the anti-ErbB-2 monoclonal antibody trastuzumab results in a synergistic antitumor effect. In this study, we addressed the mechanisms involved in this phenomenon. The activation of signaling pathways and the expression of cell cycle regulatory proteins were studied in SK-Br-3 and BT-474 breast cancer cells, following treatment with EGFR and/or ErbB-2 inhibitors. Treatment with the gefitinib/trastuzumab combination produced, as compared with a single agent, a more prolonged blockade of AKT and MAPK activation, a more pronounced accumulation of cells in the G0/G1 phase of the cell cycle, a more significant increase in the levels of p27kip1 and of hypophosphorylated pRb2, and a decrease in the levels of Cyclin D1 and survivin. Similar findings were observed with the EGFR/ErbB-2 inhibitor lapatinib. Gefitinib, trastuzumab, and their combination increased the stability of p27kip1, with the combination showing the highest effects. Blockade of both receptors with gefitinib/trastuzumab or lapatinib induced a significant increase in the levels of p27kip1 mRNA and in the nuclear levels of the p27kip1 transcription factor FKHRL-1. Inhibition of PI3K signaling also produced a significant raise in p27kip1 mRNA. Finally, down-modulation of FKHRL-1 with siRNAs prevented the lapatinib-induced increase of p27kip1 mRNA. The synergism deriving from EGFR and ErbB-2 blockade is mediated by several different alterations in the activation of signaling proteins and in the expression of cell cycle regulatory proteins, including transcriptional and posttranscriptional regulation of p27 kip1 expression. © 2009 Springer Science+Business Media, LLC.

Evangelista D.,Centro Ricerche Oncologiche Mercogliano | Evangelista D.,University of Naples Federico II | Colonna G.,The Second University of Naples | Miele M.,Centro Ricerche Oncologiche Mercogliano | And 5 more authors.
Protein Engineering, Design and Selection | Year: 2010

The cytokines, main players of the chronic inflammation progression leading to serious diseases such as diabetes or cancer, represent a target for better clinical prognosis and innovative therapeutic strategies. To investigate the immunopathogenetic progression of these diseases, the evaluation of serum cytokines profiles made of many different proteins is much more informative than single protein measurements. We developed a Clinical Data Mining Software to collect cytokine profiles evaluated on healthy subjects and patients by multiplex immunoassays also annotated with their clinical and laboratory data, to compare patient profiles by statistical tools and to evaluate their disease progression. © The Author 2010. Published by Oxford University Press. All rights reserved.

Di Bernardo G.,The Second University of Naples | Galderisi U.,The Second University of Naples | Galderisi U.,Temple University | Fiorito C.,IRCCS Multimedica | And 8 more authors.
Journal of Cellular Physiology | Year: 2010

Hematopoietic stem cells derive regulatory information also from parathyroid hormone (PTH). To explore the possibility that PTH may have a role in regulation of other stem cells residing in bone marrow, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) we assessed the effect of this hormone on the in vitro behavior of MSCs and EPCs. Weevidenced that MSCs were much more responsive to PTH than EPCs. PTH increased the proliferation rate of MSCs with a diminution of senescence and apoptosis. Taken together, our results may suggest a protective effect of PTH on MSCs that reduces stress phenomena and preserve genome integrity. At the opposite, PTH did not modify the fate of EPCs in culture. © 2009 Wiley-Liss, Inc.

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