期刊
HAEMATOLOGICA
卷 104, 期 11, 页码 2225-2240出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.201343
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资金
- Jilin University, Changchun, China
- Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
- National Natural Science Foundation of China [NSFC 31671438, NSFC 31471295]
- Hyundai Hope on Wheels, LaFontaine Family/U Can-Cer Vive Foundation
- Kids Without Cancer, Children's Hospital of Michigan Foundation
- Decerchio/Guisewite Family
- Elana Fund
- Ginopolis/Karmanos Endowment
- Ring Screw Textron Endowed Chair for Pediatric Cancer Research
- NIH Center grant [P30 CA022453]
- Justin's Gift
Induction therapy for patients with acute myeloid leukemia (AML) has remained largely unchanged for over 40 years, while overall survival rates remain unacceptably low, highlighting the need for new therapies. The PI3K/Akt pathway is constitutively active in the majority of patients with AML. Given that histone deacetylase inhibitors have been shown to synergize with PI3K inhibitors in preclinical AML models, we investigated the novel dual-acting PI3K and histone deacetylase inhibitor CUDC-907 in AML cells both in vitro and in vivo. We demonstrated that CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows in vivo efficacy in an AML cell line-derived xenograft mouse model. CUDC-907-induced apoptosis was partially dependent on Mcl-1, Bim, and c-Myc. CUDC-907 induced DNA damage in AML cells while sparing normal hematopoietic cells. Downregulation of CHK1, Wee1, and RRM1, and induction of DNA damage also contributed to CUDC-907-induced apoptosis of AML cells. In addition, CUDC-907 treatment decreased leukemia progenitor cells in primary AML samples ex vivo, while also sparing normal hematopoietic progenitor cells. These findings support the clinical development of CUDC-907 for the treatment of AML.
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