Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer

Stephen G. Chun, Weiqiang Zhou, Nelson Shu-Sang Yee

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Combined targeting of distinct cellular signaling mechanisms may improve the efficacy and reduce the toxicity of therapy in pancreatic cancer. Histone deacetylases (HDACs) control cellular functions through epigenetic modulation, and HDACs inhibitors suppress cell growth in pancreatic adenocarcinoma. The Hedgehog (Hh) pathway regulates the development of the pancreas, and aberrant Hh signaling promotes the initiation and progression of pancreatic neoplasia. We hypothesize that HDACs and the Hh pathway cooperatively interact to regulate cellular proliferation of the exocrine pancreas. A combination of the HDAC inhibitor SAHA and the Smoothened antagonist SANT-1 was evaluated for their ability to suppress growth of the Gemcitabine-resistant pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3. The combination of SAHA and SANT-1 supra-additively suppressed cellular proliferation and colony formation. Flow cytometric and immunohistochemical analyses indicated that enhanced induction of apoptotic cell death, cell cycle arrest in G 0/G 1 phase, and ductal epithelial differentiation are involved. Cell death was associated with nuclear localization of survivin, increased bax expression, and activation of caspases 3 and 7. Consistent with the cell cycle arrest and cytodifferentiation, the cyclin-dependent kinase inhibitors p21 waf and p27 kip1 were upregulated, and cyclin D1 downregulated. The potentiated anti-proliferative effect by the combination of SAHA and SANT-1 may involve cooperative suppression of the Hh pathway activity, as shown by the upregulation of HHIP by SAHA, and enhanced repression of of Ptc-1 mRNA expression. In summary, we have developed a molecular target-based therapeutic approach that overcomes chemoresistance in pancreatic cancer cells by chemically inhibiting HDACs and Hh signaling in combination.

Original languageEnglish (US)
Pages (from-to)1328-1339
Number of pages12
JournalCancer Biology and Therapy
Volume8
Issue number14
DOIs
StatePublished - Jul 15 2009

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Histone Deacetylases
Pancreatic Neoplasms
gemcitabine
Cell Cycle Checkpoints
Adenocarcinoma
Cell Death
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Caspase 7
Exocrine Pancreas
Growth Inhibitors
Cyclin D1
Epigenomics
Caspase 3
Pancreas
Up-Regulation
Down-Regulation
Cell Line
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology
  • Medicine(all)

Cite this

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abstract = "Combined targeting of distinct cellular signaling mechanisms may improve the efficacy and reduce the toxicity of therapy in pancreatic cancer. Histone deacetylases (HDACs) control cellular functions through epigenetic modulation, and HDACs inhibitors suppress cell growth in pancreatic adenocarcinoma. The Hedgehog (Hh) pathway regulates the development of the pancreas, and aberrant Hh signaling promotes the initiation and progression of pancreatic neoplasia. We hypothesize that HDACs and the Hh pathway cooperatively interact to regulate cellular proliferation of the exocrine pancreas. A combination of the HDAC inhibitor SAHA and the Smoothened antagonist SANT-1 was evaluated for their ability to suppress growth of the Gemcitabine-resistant pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3. The combination of SAHA and SANT-1 supra-additively suppressed cellular proliferation and colony formation. Flow cytometric and immunohistochemical analyses indicated that enhanced induction of apoptotic cell death, cell cycle arrest in G 0/G 1 phase, and ductal epithelial differentiation are involved. Cell death was associated with nuclear localization of survivin, increased bax expression, and activation of caspases 3 and 7. Consistent with the cell cycle arrest and cytodifferentiation, the cyclin-dependent kinase inhibitors p21 waf and p27 kip1 were upregulated, and cyclin D1 downregulated. The potentiated anti-proliferative effect by the combination of SAHA and SANT-1 may involve cooperative suppression of the Hh pathway activity, as shown by the upregulation of HHIP by SAHA, and enhanced repression of of Ptc-1 mRNA expression. In summary, we have developed a molecular target-based therapeutic approach that overcomes chemoresistance in pancreatic cancer cells by chemically inhibiting HDACs and Hh signaling in combination.",
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Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. / Chun, Stephen G.; Zhou, Weiqiang; Yee, Nelson Shu-Sang.

In: Cancer Biology and Therapy, Vol. 8, No. 14, 15.07.2009, p. 1328-1339.

Research output: Contribution to journalArticle

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