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Updated: Jun 22, 2026
High-throughput Fluorometric Measurement of Potential Soil Extracellular Enzyme Activities
Published on: November 15, 2013
[Not Available]
Lyse A Norian1, Tamara A Kucaba, James K Earel
1Department of Urology and Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently being investigated as a therapeutic agent for a variety of malignancies, as it triggers apoptosis specifically in transformed cells. However, TRAIL use as a stand alone therapeutic is hampered by the fact that many primary tumor cells are resistant to TRAIL-mediated apoptosis. Here, we investigated the extent to which pretreatment of TRAIL-resistant primary B-cell chronic lymphocytic leukemia (B-CLL) cells with histone deacetylase inhibitors (HDACis) could render them susceptible to killing by TRAIL. We found that HDAC inhibition in B-CLL cells led to increased TRAIL receptor expression, increased caspase activation, decreased expression of antiapoptotic regulators such as Bcl-2, and ultimately, enhanced TRAIL-induced apoptosis. Importantly, untransformed peripheral blood mononuclear cells remained largely resistant to TRAIL, even in the presence of HDACis. These results suggest that combination therapies using HDAC inhibition and TRAIL could prove beneficial for the treatment of B-CLL.
Insights
Histone deacetylase inhibitors (HDACis) can sensitize resistant B-cell chronic lymphocytic leukemia (B-CLL) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy. This combination enhances cancer cell death while sparing normal cells.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy by inducing apoptosis in malignant cells.
- Resistance to TRAIL-mediated apoptosis is a significant challenge for its standalone therapeutic use, particularly in primary tumor cells.
- B-cell chronic lymphocytic leukemia (B-CLL) cells often exhibit resistance to TRAIL-induced apoptosis.
Purpose of the Study:
- To investigate the efficacy of combining histone deacetylase inhibitors (HDACis) with TRAIL therapy.
- To determine if HDAC inhibition can overcome TRAIL resistance in primary B-CLL cells.
- To assess the impact of HDACis on TRAIL receptor expression and apoptotic pathways in B-CLL.
Main Methods:
- Primary B-CLL cells and peripheral blood mononuclear cells were treated with HDAC inhibitors.
- Cells were subsequently exposed to TRAIL to assess apoptosis induction.
- Expression levels of TRAIL receptors, caspases, and antiapoptotic proteins (e.g., Bcl-2) were analyzed.
Main Results:
- HDAC inhibition significantly increased TRAIL receptor expression on B-CLL cells.
- HDACis enhanced caspase activation and decreased Bcl-2 expression in B-CLL cells.
- Combination therapy resulted in enhanced TRAIL-induced apoptosis in B-CLL cells, with minimal effect on normal cells.
Conclusions:
- Pretreatment with HDAC inhibitors can sensitize TRAIL-resistant B-CLL cells to TRAIL-mediated apoptosis.
- Combination therapy of HDAC inhibitors and TRAIL presents a promising strategy for B-CLL treatment.
- This approach may offer a targeted therapeutic option with reduced toxicity to normal tissues.
