Cargando…

Antileukemic activity and mechanism of action of the novel PI3K and histone deacetylase dual inhibitor CUDC-907 in acute myeloid leukemia

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Xinyu, Su, Yongwei, Madlambayan, Gerard, Edwards, Holly, Polin, Lisa, Kushner, Juiwanna, Dzinic, Sijana H., White, Kathryn, Ma, Jun, Knight, Tristan, Wang, Guan, Wang, Yue, Yang, Jay, Taub, Jeffrey W., Lin, Hai, Ge, Yubin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821619/
https://www.ncbi.nlm.nih.gov/pubmed/30819918
http://dx.doi.org/10.3324/haematol.2018.201343
Descripción
Sumario: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.