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

Haematologica
Xinyu LiYubin Ge

Abstract

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.

Citations

Mar 23, 2020·Journal of Cell Communication and Signaling·Zhao-Jun LiFeng-Ze Wang
Oct 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Damiano CirriNicola Micale
Nov 10, 2020·Expert Opinion on Emerging Drugs·Nadya JammalNaveen Pemmaraju
Jan 7, 2021·Cancers·Luca MologniAlfonso Zambon
Nov 6, 2020·International Journal of Molecular Sciences·Kasturi RangannaZivar Yousefipour
Dec 19, 2020·Signal Transduction and Targeted Therapy·Jenna L CarterYubin Ge
Jan 5, 2021·Curēus·Christopher HillyarJajini Varghese
Mar 25, 2021·Journal of Experimental & Clinical Cancer Research : CR·Mitsuhito HiranoArinobu Tojo
May 6, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Marta SzumilakAndrzej Stanczak
Apr 23, 2020·Journal of Medicinal Chemistry·Tingting LiuGuiyun Duan

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Methods Mentioned

BETA
xenograft
transgenic
flow cytometry
acetylation
PCR

Software Mentioned

GraphPad Prism

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