Selective inhibition of histone deacetylases 1/2/6 in combination with gemcitabine: A promising combination for pancreatic cancer therapy

Richard S. Laschanzky, Lisa E. Humphrey, Jihyun Ma, Lynette M. Smith, Thomas J. Enke, Surendra K. Shukla, Aneesha Dasgupta, Pankaj K. Singh, Gillian M. Howell, Michael G. Brattain, Quan P. Ly, Adrian R. Black, Jennifer D. Black

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical effcacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic effcacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.

Original languageEnglish (US)
Article number1327
JournalCancers
Volume11
Issue number9
DOIs
StatePublished - Sep 2019

Fingerprint

gemcitabine
Histone Deacetylases
Pancreatic Neoplasms
Adenocarcinoma
Histone Deacetylase Inhibitors
Therapeutic Uses
Therapeutics
Cell Line
Drug Combinations
Heterografts
Small Interfering RNA

Keywords

  • Gemcitabine
  • HDAC
  • Histone deacetylase
  • Histone deacetylase inhibitor
  • Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Selective inhibition of histone deacetylases 1/2/6 in combination with gemcitabine : A promising combination for pancreatic cancer therapy. / Laschanzky, Richard S.; Humphrey, Lisa E.; Ma, Jihyun; Smith, Lynette M.; Enke, Thomas J.; Shukla, Surendra K.; Dasgupta, Aneesha; Singh, Pankaj K.; Howell, Gillian M.; Brattain, Michael G.; Ly, Quan P.; Black, Adrian R.; Black, Jennifer D.

In: Cancers, Vol. 11, No. 9, 1327, 09.2019.

Research output: Contribution to journalArticle

Laschanzky, Richard S. ; Humphrey, Lisa E. ; Ma, Jihyun ; Smith, Lynette M. ; Enke, Thomas J. ; Shukla, Surendra K. ; Dasgupta, Aneesha ; Singh, Pankaj K. ; Howell, Gillian M. ; Brattain, Michael G. ; Ly, Quan P. ; Black, Adrian R. ; Black, Jennifer D. / Selective inhibition of histone deacetylases 1/2/6 in combination with gemcitabine : A promising combination for pancreatic cancer therapy. In: Cancers. 2019 ; Vol. 11, No. 9.
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AU - Laschanzky, Richard S.

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AU - Ma, Jihyun

AU - Smith, Lynette M.

AU - Enke, Thomas J.

AU - Shukla, Surendra K.

AU - Dasgupta, Aneesha

AU - Singh, Pankaj K.

AU - Howell, Gillian M.

AU - Brattain, Michael G.

AU - Ly, Quan P.

AU - Black, Adrian R.

AU - Black, Jennifer D.

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AB - Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical effcacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic effcacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.

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