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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/24404

Title: Synergistic activity of everolimus and 5-aza-2 '-deoxycytidine in medullary thyroid carcinoma cell lines
Authors: Vitale, Giovanni
Dicitore, Alessandra
Pepe, Daniele
Gentilini, Davide
Grassi, Elisa S.
Borghi, Maria O.
Gelmini, Giulia
Cantone, Maria C.
Gaudenzi, Germano
Misso, Gabriella
Di Blasio, Anna M.
Hofland, Leo J.
Caraglia, Michele
Persani, Luca
Issue Date: 2017
Publisher: WILEY
Citation: MOLECULAR ONCOLOGY, 11(8), p. 1007-1022
Abstract: Medullary thyroid cancer (MTC) is a tumor highly resistant to chemo-and radiotherapy. Drug resistance can be induced by epigenetic changes such as aberrant DNA methylation. To overcome drug resistance, we explored a promising approach based on the use of 5-aza-2'-deoxycytidine (AZA), a demethylating agent, in combination with the mTOR inhibitor everolimus in MTC cells (MZ-CRC-1 and TT). This combined treatment showed a strong synergistic antiproliferative activity through the induction of apoptosis. The effect of everolimus and/or AZA on genome-wide expression profiling was evaluated by Illumina BeadChip in MZ-CRC-1 cells. An innovative bioinformatic pipeline identified four potential molecular pathways implicated in the synergy between AZA and everolimus: PI3K-Akt signaling, the neurotrophin pathway, ECM/receptor interaction, and focal adhesion. Among these, the neurotrophin signaling pathway was most directly involved in apoptosis, through the overexpression of NGFR and Bax genes. The increased expression of genes involved in the NGFRMAPK10-TP53-Bax/Bcl2 pathway during incubation with AZA plus everolimus was validated by western blotting in MZ-CRC-1 cells. Interestingly, addition of a neutralizing anti-NGFR antibody inhibited the synergistic cytotoxic activity between AZA and everolimus. These results open a new therapeutic scenario for MTC and potentially other neuroendocrine tumors, where therapy with mTOR inhibitors is currently approved.
Notes: [Vitale, Giovanni; Grassi, Elisa S.; Borghi, Maria O.; Cantone, Maria C.; Gaudenzi, Germano; Persani, Luca] Univ Milan, Dept Clin Sci & Community Hlth DISCCO, Milan, Italy. [Vitale, Giovanni; Dicitore, Alessandra; Gelmini, Giulia; Persani, Luca] Ist Auxol Italiano IRCCS, Lab Endocrine & Metab Res, Milan, Italy. [Pepe, Daniele] Hasselt Univ, I BioStat, Hasselt, Belgium. [Gentilini, Davide; Di Blasio, Anna M.] Ist Auxol Italiano, Mol Biol Lab, Milan, Italy. [Borghi, Maria O.] Ist Auxol Italiano IRCCS, Expt Lab Immunorheumatol Res, Milan, Italy. [Misso, Gabriella; Caraglia, Michele] Univ Naples 2, Dept Biochem Biophys & Gen Pathol, Naples, Italy. [Hofland, Leo J.] Erasmus MC, Sect Endocrinol, Dept Internal Med, Rotterdam, Netherlands.
URI: http://hdl.handle.net/1942/24404
DOI: 10.1002/1878-0261.12070
ISI #: 000406633900008
ISSN: 1878-0261
Category: A1
Type: Journal Contribution
Validation: ecoom, 2018
Appears in Collections: Research publications

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