Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy
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 reduc...
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doaj-9f404c78c65f4f78b7440ae7df6405632020-11-25T01:35:56ZengMDPI AGCancers2072-66942019-09-01119132710.3390/cancers11091327cancers11091327Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer TherapyRichard S. Laschanzky0Lisa E. Humphrey1Jihyun Ma2Lynette M. Smith3Thomas J. Enke4Surendra K. Shukla5Aneesha Dasgupta6Pankaj K. Singh7Gillian M. Howell8Michael G. Brattain9Quan P. Ly10Adrian R. Black11Jennifer D. Black12Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USAPancreatic 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.https://www.mdpi.com/2072-6694/11/9/1327pancreatic ductal adenocarcinomahistone deacetylaseHDAChistone deacetylase inhibitorgemcitabine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy Cancers pancreatic ductal adenocarcinoma histone deacetylase HDAC histone deacetylase inhibitor gemcitabine |
author_facet |
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 |
author_sort |
Richard S. Laschanzky |
title |
Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy |
title_short |
Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy |
title_full |
Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy |
title_fullStr |
Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy |
title_full_unstemmed |
Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy |
title_sort |
selective inhibition of histone deacetylases 1/2/6 in combination with gemcitabine: a promising combination for pancreatic cancer therapy |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-09-01 |
description |
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. |
topic |
pancreatic ductal adenocarcinoma histone deacetylase HDAC histone deacetylase inhibitor gemcitabine |
url |
https://www.mdpi.com/2072-6694/11/9/1327 |
work_keys_str_mv |
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