Pancreatic ductal adenocarcinoma (PDAC) is quite resistant to conventional treatments, and gemcitabine, the standard chemotherapeutic agent, offers only a small benefit. Development and progression of PDAC are complex processes involving dysregulation of multiple signal transduction pathways arising from not only genetic but also epigenetic alterations. This makes the epigenetic approach to the treatment of PDAC of great interest. Histone deacetylases, a family of enzymes that, by removal of acetyl groups from a variety of histone and nonhistone proteins, play an important role in the epigenetic regulation of gene expression, are frequently dysregulated in PDAC. In particular, overexpression of class I histone deacetylases has been related to higher tumor grade, poor prognosis and development of chemoresistance. Histone deacetylase inhibitors (HDACIs), a novel class of agents endowed with pleiotropic antitumor effects, appear promising either for their preferential toxicity towards transformed as compared to normal cells and their ability to synergistically enhance the anticancer activity of radiotherapy and many chemotherapeutic agents. Many HDACIs have been shown to increase the antiproliferative and proapoptotic effects of gemcitabine, 5-fluorouracil and bortezomib, a new proteasome inhibitor, in vitro and in vivo PDAC xenograft models. MGCD0103, romidepsin, panobinostat, vorinostat and valproic acid, are currently being tested in association with radiotherapy or chemotherapy (gemcitabine, fluoropyrimidines, proteasome inhibitors) in phase I-II clinical trials in patients with locally advanced or metastatic PDAC.

An Epigenetic Approach to Pancreatic Cancer Treatment: the Prospective Role of Histone Deacetylase Inhibitors

TINARI, Nicola;DE TURSI, Michele;GRASSADONIA, Antonino;STUPPIA, Liborio;IACOBELLI, Stefano;NATOLI, Clara
2012-01-01

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is quite resistant to conventional treatments, and gemcitabine, the standard chemotherapeutic agent, offers only a small benefit. Development and progression of PDAC are complex processes involving dysregulation of multiple signal transduction pathways arising from not only genetic but also epigenetic alterations. This makes the epigenetic approach to the treatment of PDAC of great interest. Histone deacetylases, a family of enzymes that, by removal of acetyl groups from a variety of histone and nonhistone proteins, play an important role in the epigenetic regulation of gene expression, are frequently dysregulated in PDAC. In particular, overexpression of class I histone deacetylases has been related to higher tumor grade, poor prognosis and development of chemoresistance. Histone deacetylase inhibitors (HDACIs), a novel class of agents endowed with pleiotropic antitumor effects, appear promising either for their preferential toxicity towards transformed as compared to normal cells and their ability to synergistically enhance the anticancer activity of radiotherapy and many chemotherapeutic agents. Many HDACIs have been shown to increase the antiproliferative and proapoptotic effects of gemcitabine, 5-fluorouracil and bortezomib, a new proteasome inhibitor, in vitro and in vivo PDAC xenograft models. MGCD0103, romidepsin, panobinostat, vorinostat and valproic acid, are currently being tested in association with radiotherapy or chemotherapy (gemcitabine, fluoropyrimidines, proteasome inhibitors) in phase I-II clinical trials in patients with locally advanced or metastatic PDAC.
File in questo prodotto:
File Dimensione Formato  
Natoli_CCDT An Epigenetic Approach.pdf

Solo gestori archivio

Tipologia: Documento in Post-print
Dimensione 398.47 kB
Formato Adobe PDF
398.47 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11564/236423
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 34
  • ???jsp.display-item.citation.isi??? 30
social impact