期刊
CANCERS
卷 12, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/cancers12092400
关键词
acute myeloid leukemia; Bcl-2; venetoclax; IACS-010759; oxidative phosphorylation
类别
资金
- School of Life Sciences of Jilin University
- Ginopolis/Karmanos Endowment
- Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
- NIH Center Grant [P30 CA022453]
- Ring Screw Textron Endowed Chair for Pediatric Cancer Research
- Children's Hospital of Michigan Foundation
- Kids Without Cancer
- LaFontaine Family/U Can-Cer Vive Foundation
- Decerchio/Guisewite Family
- Elana Fund
Targeting oxidative phosphorylation (OXPHOS) is a promising strategy to improve treatment outcomes of acute myeloid leukemia (AML) patients. IACS-010759 is a mitochondrial complex I inhibitor that has demonstrated preclinical antileukemic activity and is being tested in Phase I clinical trials. However, complex I deficiency has been reported to inhibit apoptotic cell death through prevention of cytochrome c release. Thus, combining IACS-010759 with a BH3 mimetic may overcome this mechanism of resistance leading to synergistic antileukemic activity against AML. In this study, we show that IACS-010759 and venetoclax synergistically induce apoptosis in OXPHOS-reliant AML cell lines and primary patient samples and cooperatively target leukemia progenitor cells. In a relatively OXPHOS-reliant AML cell line derived xenograft mouse model, IACS-010759 treatment significantly prolonged survival, which was further enhanced by treatment with IACS-010759 in combination with venetoclax. Consistent with our hypothesis, IACS-010759 treatment indeed retained cytochrome c in mitochondria, which was completely abolished by venetoclax, resulting in Bak/Bax- and caspase-dependent apoptosis. Our preclinical data provide a rationale for further development of the combination of IACS-010759 and venetoclax for the treatment of patients with AML.
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