ArticleCell death and differentiation2020
Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways.
Article in Cell death and differentiation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 28 citations in OpenAlex.
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- Epigenetic Priming by Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-cell Lymphoma.Cancer research communications · 2024Article
- Clinically used drug arsenic trioxide targets XIAP and overcomes apoptosis resistance in an organoid-based preclinical cancer model.Chemical science · 2024Article
- NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression.Cell death discovery · 2024Article
- Heterocyclic Molecular Targeted Drugs and Nanomedicines for Cancer: Recent Advances and Challenges.Pharmaceutics · 2023Review
- Generalist in allogeneic hematopoietic stem cell transplantation for MDS or AML: Epigenetic therapy.Frontiers in immunology · 2022Review
- Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies.Discover oncology · 2021Review
- The non-peptidomimetic IAP antagonist ASTX660 sensitizes colorectal cancer cells for extrinsic apoptosis.FEBS open bio · 2021Article
- Withaferin A and Ovarian Cancer Antagonistically Regulate Skeletal Muscle Mass.Frontiers in cell and developmental biology · 2021Article
- DNA Methyltransferases in Cancer: Biology, Paradox, Aberrations, and Targeted Therapy.Cancers · 2020Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS, and BAX. Individual knockdown of the death receptors TNFR1, DR5, and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASLG) failed to provide protection. Also, TNFα-blocking antibody Enbrel had little protective effect on SGI-110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660-triggered loss of mitochondrial membrane potential (MMP) and BAX activation which contributes to cell death, as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in the activation of caspases-3/-7, nuclear fragmentation, and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.
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