2. Academic Validation
  3. Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

  • Cancers (Basel). 2019 Sep 7;11(9):1327. doi: 10.3390/cancers11091327.
Richard S Laschanzky 1,  Lisa E Humphrey 2,  Jihyun Ma 3,  Lynette M Smith 4,  Thomas J Enke 5,  Surendra K Shukla 6,  Aneesha Dasgupta 7,  Pankaj K Singh 8,  Gillian M Howell 9,  Michael G Brattain 10,  Quan P Ly 11,  Adrian R Black 12,  Jennifer D Black 13
Affiliations

Affiliations

  • 1 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. rlaschan@unmc.edu.
  • 2 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. lbrattain@unmc.edu.
  • 3 Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA. jihyun.ma@unmc.edu.
  • 4 Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA. lmsmith@unmc.edu.
  • 5 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. thomas.enke@unmc.edu.
  • 6 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. surendra.shukla@unmc.edu.
  • 7 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. aneesha.dasgupta@unmc.edu.
  • 8 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. Pankaj.Singh@unmc.edu.
  • 9 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. gillian.howell@nmhs.org.
  • 10 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 11 Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA. qly@unmc.edu.
  • 12 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. adrian.black@unmc.edu.
  • 13 Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. jennifer.black@unmc.edu.
PMID: 31500290 DOI: 10.3390/cancers11091327
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 efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. 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.

Keywords

HDAC; gemcitabine; histone deacetylase; histone deacetylase inhibitor; pancreatic ductal adenocarcinoma.

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