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Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma
- Source :
- Oncogenesis 7 (2018): 20. doi:10.1038/s41389-018-0026-x, info:cnr-pdr/source/autori:Di Martile, Marta; Desideri, Marianna; Tupone, Maria Grazia; Buglioni, Simonetta; Antoniani, Barbara; Mastroiorio, Carlotta; Falcioni, Rita; Ferraresi, Virginia; Baldini, Nicola; Biagini, Roberto; Milella, Michele; Trisciuoglio, Daniela; Del Bufalo, Donatella/titolo:Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma./doi:10.1038%2Fs41389-018-0026-x/rivista:Oncogenesis/anno:2018/pagina_da:20/pagina_a:/intervallo_pagine:20/volume:7, Oncogenesis, Vol 7, Iss 2, Pp 1-14 (2018), Oncogenesis
- Publication Year :
- 2018
- Publisher :
- Macmillan Publishers Limited, Stati Uniti d'America, 2018.
-
Abstract
- Sarcomas are rare tumors with generally poor prognosis, for which current therapies have shown limited efficacy. Histone deacetylase inhibitors (HDACi) are emerging anti-tumor agents; however, little is known about their effect in sarcomas. By using established and patient-derived sarcoma cells with different subtypes, we showed that the pan-HDACi, ITF2357, potently inhibited in vitro survival in a p53-independent manner. ITF2357-mediated cell death implied the activation of mitochondrial apoptosis, as attested by induction of pro-apoptotic BH3-only proteins and a caspases-dependent mechanism. ITF2357 also induced autophagy, which protected sarcoma cells from apoptotic cell death. ITF2357 activated forkhead box (FOXO) 1 and 3a transcription factors and their downstream target genes, however, silencing of both FOXO1 and 3a did not protect sarcoma cells against ITF2357-induced apoptosis and upregulated FOXO4 and 6. Notably, ITF2357 synergized with Doxorubicin to induce cell death of established and patient-derived sarcoma cells. Furthermore, combination treatment strongly impaired xenograft tumor growth in vivo, when compared to single treatments, suggesting that combination of ITF2357 with Doxorubicin has the potential to enhance sensitization in different preclinical models of sarcoma. Overall, our study highlights the therapeutic potential of ITF2357, alone or in rational combination therapies, for bone and soft tissue sarcomas management.
- Subjects :
- 0301 basic medicine
Cancer Research
Programmed cell death
sarcoma
medicine.drug_class
lcsh:RC254-282
Article
combination therapy
03 medical and health sciences
0302 clinical medicine
HDAC inhibitor
Medicine
Doxorubicin
Molecular Biology
business.industry
Histone deacetylase inhibitor, apoptosis, sarcoma, epigenetics
Histone deacetylase inhibitor
Autophagy
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Histone
030104 developmental biology
Apoptosis
030220 oncology & carcinogenesis
FOXO4
Cancer research
Histone deacetylase
Sarcoma
business
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Oncogenesis 7 (2018): 20. doi:10.1038/s41389-018-0026-x, info:cnr-pdr/source/autori:Di Martile, Marta; Desideri, Marianna; Tupone, Maria Grazia; Buglioni, Simonetta; Antoniani, Barbara; Mastroiorio, Carlotta; Falcioni, Rita; Ferraresi, Virginia; Baldini, Nicola; Biagini, Roberto; Milella, Michele; Trisciuoglio, Daniela; Del Bufalo, Donatella/titolo:Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma./doi:10.1038%2Fs41389-018-0026-x/rivista:Oncogenesis/anno:2018/pagina_da:20/pagina_a:/intervallo_pagine:20/volume:7, Oncogenesis, Vol 7, Iss 2, Pp 1-14 (2018), Oncogenesis
- Accession number :
- edsair.doi.dedup.....6cdc3030831bca0ac7808a9a48bfaa7f