Journal
ONCOTARGET
Volume 8, Issue 37, Pages 61761-61776Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.18688
Keywords
NHL; ONC201; TIC10; TRAIL; cancer
Categories
Funding
- Drs. Martin and Dorothy Spatz Foundation
- Oncoceutics, Inc.
- Blanche Bender Professorship in Cancer Research
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Cutaneous T-cell lymphomas (CTCLs) are extremely symptomatic and still incurable, and more effective and less toxic therapies are urgently needed. ONC201, an imipridone compound, has shown efficacy in pre-clinical studies in multiple advanced cancers. This study was to evaluate the anti-tumor activity of ONC201 on CTCL cells. The effect of ONC201 on the cell growth and apoptosis were evaluated in CTCL cell lines (n=8) and primary CD4(+) malignant T cells isolated from CTCL patients (n=5). ONC201 showed a time-dependent cell growth inhibition in all treated cell lines with a concentration range of 1.25-10.0 mu M. ONC201 also induced apoptosis in tested cells with a narrow concentration range of 2.5-10.0 mu M, evidenced by increased Annexin V+ cells, accompanied by accumulated sub-G1 portions. ONC201 only induced apoptosis in CD4(+) malignant T cells, not in normal CD4(+) T cells. The activating transcription factor 4 (ATF4), a hallmark of integrated stress response, was upregulated in response to ONC201 whereas Akt was downregulated. In addition, molecules in JAK/STAT and NF-kappa B pathways, as well as IL-32 beta, were downregulated following ONC201 treatment. Thus, ONC201 exerts a potent and selective anti-tumor effect on CTCL cells. Its efficacy may involve activating integrated stress response through ATF4 and inactivating JAK/STAT and NF-kappa B pathways.
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