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 NGFR-MAPK10-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.
| Original language | English |
|---|---|
| Pages (from-to) | 1007-1022 |
| Number of pages | 16 |
| Journal | Molecular Oncology |
| Volume | 11 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 1 2017 |
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Keywords
- 5-aza-2′-deoxycytidine
- everolimus
- medullary thyroid cancer
- mTOR
- neurotrophin pathway
- NGFR
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Cancer Research
Cite this
Synergistic activity of everolimus and 5-aza-2′-deoxycytidine in medullary thyroid carcinoma cell lines. / 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.
In: Molecular Oncology, Vol. 11, No. 8, 01.08.2017, p. 1007-1022.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synergistic activity of everolimus and 5-aza-2′-deoxycytidine in medullary thyroid carcinoma cell lines
AU - Vitale, Giovanni
AU - Dicitore, Alessandra
AU - Pepe, Daniele
AU - Gentilini, Davide
AU - Grassi, Elisa S.
AU - Borghi, Maria O.
AU - Gelmini, Giulia
AU - Cantone, Maria C.
AU - Gaudenzi, Germano
AU - Misso, Gabriella
AU - Di Blasio, Anna M.
AU - Hofland, Leo J.
AU - Caraglia, Michele
AU - Persani, Luca
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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 NGFR-MAPK10-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.
AB - 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 NGFR-MAPK10-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.
KW - 5-aza-2′-deoxycytidine
KW - everolimus
KW - medullary thyroid cancer
KW - mTOR
KW - neurotrophin pathway
KW - NGFR
UR - http://www.scopus.com/inward/record.url?scp=85021238302&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021238302&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.12070
DO - 10.1002/1878-0261.12070
M3 - Article
AN - SCOPUS:85021238302
VL - 11
SP - 1007
EP - 1022
JO - Molecular Oncology
JF - Molecular Oncology
SN - 1574-7891
IS - 8
ER -