Related Experiment Video
Updated: Mar 29, 2026
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Identification of HDAC6-Selective Inhibitors of Low Cancer Cell Cytotoxicity
Irina N Gaisina1,2, Werner Tueckmantel2, Andrey Ugolkov3
1Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Abstract:
The histone deacetylases (HDACs) occur in 11 different isoforms, and these enzymes regulate the activity of a large number of proteins involved in cancer initiation and progression. The discovery of isoform-selective HDAC inhibitors (HDACIs) is desirable, as it is likely that such compounds would avoid some of the undesirable side effects found with the first-generation inhibitors. A series of HDACIs previously reported by us were found to display some selectivity for HDAC6 and to induce cell-cycle arrest and apoptosis in pancreatic cancer cells. In the present work, we show that structural modification of these isoxazole-based inhibitors leads to high potency and selectivity for HDAC6 over HDAC1-3 and HDAC10, while unexpectedly abolishing their ability to block cell growth. Three inhibitors with lower HDAC6 selectivity inhibit the growth of cell lines BxPC3 and L3.6pl, and they only induce apoptosis in L3.6pl cells. We conclude that HDAC6 inhibition alone is insufficient for disruption of cell growth, and that some degree of class 1 HDAC inhibition is required. Moreover, the highly selective HDAC6Is reported herein that are weakly cytotoxic may find use in cancer immune system reactivation.
Insights
Targeted histone deacetylase inhibitors (HDACIs) show high selectivity for HDAC6 but do not inhibit cancer cell growth. Class 1 HDAC inhibition is necessary for disrupting cell growth, suggesting potential for immune reactivation therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Histone deacetylases (HDACs) are enzymes involved in cancer progression.
- Developing isoform-selective HDAC inhibitors (HDACIs) is crucial to minimize side effects.
- Previous HDACIs showed some selectivity for HDAC6 and induced apoptosis in pancreatic cancer cells.
Purpose of the Study:
- To investigate the impact of structural modifications on isoxazole-based HDACIs.
- To determine the role of HDAC6 inhibition in cancer cell growth and apoptosis.
- To explore the therapeutic potential of highly selective HDAC6 inhibitors.
Main Methods:
- Synthesis and structural modification of isoxazole-based HDACIs.
- Assays to determine HDAC isoform selectivity (HDAC6 vs. HDAC1-3, HDAC10).
- Cell-based assays to evaluate inhibition of cell growth and induction of apoptosis in pancreatic cancer cell lines (BxPC3, L3.6pl).
Main Results:
- Structural modifications yielded potent and selective HDAC6 inhibitors (HDAC6Is).
- Highly selective HDAC6Is unexpectedly lost their ability to inhibit cancer cell growth.
- HDACIs with lower HDAC6 selectivity inhibited cell growth and induced apoptosis in a cell-specific manner.
- HDAC6 inhibition alone was insufficient for disrupting cell growth.
Conclusions:
- A degree of class 1 HDAC inhibition is required for disrupting cancer cell growth.
- Highly selective HDAC6Is, while not directly cytotoxic, may be useful for cancer immune system reactivation.
- Isoform-specific HDAC inhibition offers a nuanced approach to cancer therapy development.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:34Inhibition of CDK Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...