2. Academic Validation
  3. AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis

AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis

  • Hematology. 2023 Dec;28(1):2214465. doi: 10.1080/16078454.2023.2214465.
Yunjian Li 1 2 3,  Liang Du 1 2 3,  Kaiqin Ye 2 3,  Xiao Sun 2 3,  Lei Hu 2 3,  Shan Gao 1,  Haiming Dai 1 2 3
Affiliations

Affiliations

  • 1 Basic Medicine College, Anhui Medical University, Hefei, People's Republic of China.
  • 2 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, People's Republic of China.
  • 3 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, People's Republic of China.
PMID: 37222135 DOI: 10.1080/16078454.2023.2214465
Abstract

The MCL1 inhibitors are undergoing clinical testing for multiple leukemia. However, because that MCL1 inhibition has on-target hematopoietic, hepatic and cardiac toxicities, there is substantial interest in finding agents can sensitize leukemia cells to the MCL1 inhibitors. Here we describe that the Akt inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Further experiments demonstrate that MK-2206 and Gsk690693 sensitize S63845 through the mitochondrial Apoptosis pathway. Moreover, MK-2206 downregulates the anti-apoptotic protein BCLXL and induces the BH3-only pro-apoptotic protein BAD dephosphorylation and mitochondrial translocation. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced Apoptosis, with the mechanisms involving BAD dephosphorylation and BCLXL downregulation.

Keywords

AKT; BAD; BCL2 family; MK-2206; S63845.

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