HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Synergistic inhibition of pancreatic adenocarcinoma cell growth by trichostatin A and gemcitabine.

Abstract
We investigated the ability of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to interact with gemcitabine (GEM) in inducing pancreatic cancer cell death. The combined treatment with TSA and GEM synergistically inhibited growth of four pancreatic adenocarcinoma cell lines and induced apoptosis. This effect was associated with the induction of reactive oxygen species (ROS) by GEM, increased expression of the pro-apoptotic BIM gene by both TSA and GEM and downregulation of the 5'-nucleotidase UMPH type II gene by TSA. The expression of other genes critical for GEM resistance (nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ribonucleotide reductase genes) was not affected by TSA. The functional role of ROS in cell growth inhibition by GEM was supported by (i) a significantly reduced GEM-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine, and (ii) a positive correlation between the basal level of ROS and sensitivity to GEM in 10 pancreatic cancer cell lines. The functional role of both Bim and 5'-nucleotidase UMPH type II in cell growth inhibition by TSA and GEM was assessed by RNA interference assays. In vivo studies on xenografts of pancreatic adenocarcinoma cells in nude mice showed that the association of TSA and GEM reduced to 50% the tumour mass and did not cause any apparent form of toxicity, while treatments with TSA or GEM alone were ineffective. In conclusion, the present study demonstrates a potent anti-tumour activity of TSA/GEM combination against pancreatic cancer cells in vitro and in vivo, strongly supporting the use of GEM in combination with an HDAC inhibitor for pancreatic cancer therapy.
AuthorsMassimo Donadelli, Chiara Costanzo, Stefania Beghelli, Maria Teresa Scupoli, Mario Dandrea, Antonio Bonora, Paolo Piacentini, Alfredo Budillon, Michele Caraglia, Aldo Scarpa, Marta Palmieri
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1773 Issue 7 Pg. 1095-106 (Jul 2007) ISSN: 0006-3002 [Print] Netherlands
PMID17555830 (Publication Type: Journal Article)
Chemical References
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Enzyme Inhibitors
  • Glycoproteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • Deoxycytidine
  • trichostatin A
  • 5'-Nucleotidase
  • NT5C3A protein, human
  • Gemcitabine
Topics
  • 5'-Nucleotidase (genetics, metabolism)
  • Adenocarcinoma (metabolism, pathology)
  • Animals
  • Apoptosis (physiology)
  • Apoptosis Regulatory Proteins (metabolism)
  • Bcl-2-Like Protein 11
  • Cell Cycle (physiology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Deoxycytidine (analogs & derivatives, metabolism, pharmacology)
  • Enzyme Inhibitors (metabolism, pharmacology)
  • Glycoproteins (genetics, metabolism)
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids (metabolism, pharmacology)
  • Membrane Proteins (metabolism)
  • Mice
  • Pancreatic Neoplasms (metabolism, pathology)
  • Proto-Oncogene Proteins (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Gemcitabine

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: