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Updated: May 17, 2026
Detection of Mitochondria Membrane Potential to Study CLIC4 Knockdown-induced HN4 Cell Apoptosis In Vitro
Published on: July 17, 2018
Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor
L M Lindqvist1, I Vikström, J M Chambers
1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. lindqvist@wehi.edu.au
Abstract:
There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells.
Insights
Translation inhibitors show promise for cancer treatment but can harm immune cells. This study reveals their toxicity to B cells and neutrophils via apoptosis, with T-cell death occurring through alternative pathways.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Protein synthesis inhibitors are explored for cancer therapy, particularly hematological malignancies.
- Compounds like homoharringtonine and silvestrol target translation, with Mcl-1 reduction proposed as a key mechanism for cell death.
Purpose of the Study:
- To investigate the precise mechanisms of cell death induced by translation inhibitors.
- To define the contribution of translation inhibitors to neutropenia and lymphopenia.
- To evaluate the role of Mcl-1 reduction and the Bax/Bak pathway in translation inhibitor-induced cytotoxicity.
Main Methods:
- Treatment of primary B cells, neutrophils, and T lymphocytes with translation inhibitors.
- Assessment of apoptosis using the Bax/Bak-mediated pathway.
- Evaluation of Mcl-1 levels and their correlation with cytotoxicity.
- Analysis of clonogenic survival independent of Bax/Bak-mediated apoptosis.
Main Results:
- Primary B cells and neutrophils are highly sensitive to translation inhibitors, undergoing Bax/Bak-mediated apoptosis.
- Mcl-1 reduction did not significantly enhance cytotoxicity, questioning its principal role in cell death.
- T lymphocyte killing was less dependent on Bax and Bak, indicating alternative cell death mechanisms.
- Loss of clonogenic survival was independent of Bax/Bak-mediated apoptosis.
Conclusions:
- Translation inhibitors exhibit significant cytotoxicity towards differentiated non-cycling cells, including immune cells.
- The Bax/Bak pathway is critical for B cell and neutrophil death but not entirely for T cell death or clonogenic survival.
- Mcl-1 reduction is not the primary driver of cytotoxicity, cautioning against assuming causality from correlation.
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