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Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for
Richard S Laschanzky1, Lisa E Humphrey2, Jihyun Ma3
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA. rlaschan@unmc.edu.
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.
Insights
Targeting multiple histone deacetylases (HDACs), specifically HDACs 1, 2, and 6, shows promise for enhancing pancreatic cancer therapy when combined with gemcitabine, offering a potential new strategy for this deadly disease.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to limited effective treatments.
- Pan-histone deacetylase (HDAC) inhibitors show preclinical promise but clinical use is limited by toxicity.
- Selective HDAC inhibition may offer a safer therapeutic approach for PDAC.
Purpose of the Study:
- To identify specific HDACs mediating therapeutic effects in PDAC.
- To evaluate synergistic effects of combined HDAC inhibitors and gemcitabine.
- To support the development of novel HDAC-targeted therapies for PDAC.
Main Methods:
- Drug synergy assays with Mocetinostat (HDAC1/2/3 inhibitor) and LMK-235 (HDAC4/5/6 inhibitor) in PDAC cell lines.
- siRNA-mediated knockdown to identify key HDAC targets.
- Combination therapy studies with gemcitabine, Romidepsin (HDAC1/2 inhibitor), and ACY-1215 (HDAC6 inhibitor).
- In vivo studies using PDAC xenografts.
Main Results:
- Mocetinostat and LMK-235 synergized in PDAC cell lines.
- The combination of Mocetinostat, LMK-235, and gemcitabine demonstrated strong synergy.
- Synergy was linked to the inhibition of HDACs 1, 2, and 6.
- Pharmacological inhibition of HDACs 1, 2, and 6 synergized with gemcitabine, enhancing anti-PDAC effects in vitro and in vivo.
Conclusions:
- Inhibition of multiple HDACs (1, 2, and 6) is crucial for the therapeutic efficacy of HDAC inhibitors in PDAC.
- Combined inhibition of HDACs 1, 2, and 6 with gemcitabine represents a promising therapeutic strategy for PDAC.
- Further development of novel strategies targeting these specific HDACs is warranted for PDAC treatment.
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