HDAC Class I Inhibitor Domatinostat Induces Apoptosis Preferentially in Glioma Stem Cells Through p53-Dependent and
Yurika Nakagawa-Saito1, Yasufumi Ito1,2, Kazuki Nakamura1,3
1Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Abstract:
Domatinostat is an inhibitor of class I histone deacetylases, whose safety and efficacy as a cancer therapeutic has been demonstrated in a recent phase II study in patients with esophagogastric adenocarcinoma. We previously showed that domatinostat exhibited preferential cytotoxic activity against glioma stem cells (GSCs) compared to their differentiated counterparts. However, the underlying mechanism behind the preferential cytotoxicity is yet to be elucidated. In this study, we examined the effects of domatinostat treatment, as well as those of the knockdown of p53 or BAX or of the overexpression of BAX, on the expression of p53, BAX, and cleaved caspase substrates and on cell death in GSCs and their isogenic, differentiated counterparts. The results obtained indicated that domatinostat induced caspase-dependent apoptotic cell death preferentially in GSCs, which was accompanied by increased BAX expression in GSCs, but not in their differentiated counterparts. The increased BAX expression was required for domatinostat-induced GSC death, whereas BAX overexpression was sufficient to induce cell death in both GSCs and their differentiated counterparts. Notably, the expression of BAX after domatinostat treatment showed an early, p53-independent increase followed by a late, p53-dependent one. Together, the results suggest that the unique ability of domatinostat to activate the p53-dependent and -independent programs of BAX expression selectively in GSCs could account for its preferential cytotoxicity against GSCs. Our findings may also help guide the selection of patients with glioblastoma, and possibly those with other types of cancer, who are most likely to benefit from domatinostat treatment and optimize the treatment strategy for such patients.
Insights
Domatinostat preferentially kills glioma stem cells (GSCs) through a caspase-dependent apoptosis pathway. This effect relies on BAX expression, activated by both p53-dependent and -independent mechanisms unique to GSCs.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Domatinostat, a histone deacetylase inhibitor, shows promise in cancer therapy.
- Previous studies indicated domatinostat's preferential cytotoxicity against glioma stem cells (GSCs).
- The mechanism for this selective GSC cytotoxicity remained unclear.
Purpose of the Study:
- To elucidate the mechanism behind domatinostat's preferential cytotoxicity in GSCs.
- To investigate the roles of p53 and BAX in domatinostat-induced cell death.
- To analyze the impact of domatinostat on GSCs versus differentiated counterparts.
Main Methods:
- Examined domatinostat effects on p53, BAX, and caspase substrate expression.
- Utilized knockdown of p53 or BAX, and overexpression of BAX.
- Compared responses in GSCs and their isogenic, differentiated counterparts.
Main Results:
- Domatinostat induced preferential caspase-dependent apoptosis in GSCs.
- Increased BAX expression was observed in GSCs but not differentiated cells, and was required for GSC death.
- BAX overexpression alone caused cell death in both GSC and differentiated cells.
- Domatinostat-induced BAX expression occurred via early p53-independent and late p53-dependent pathways.
Conclusions:
- Domatinostat's selective GSC cytotoxicity is attributed to its ability to activate p53-dependent and -independent BAX expression programs.
- Findings suggest domatinostat's potential for treating glioblastoma and other cancers.
- Results may aid in patient selection and optimizing domatinostat treatment strategies.
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