Frontiers in Oncology (Apr 2020)

The PI3K/AKT Pathway Inhibitor ISC-4 Induces Apoptosis and Inhibits Growth of Leukemia in Preclinical Models of Acute Myeloid Leukemia

  • Charyguly Annageldiyev,
  • Charyguly Annageldiyev,
  • Su-Fern Tan,
  • Shreya Thakur,
  • Pavan Kumar Dhanyamraju,
  • Srinivasa R. Ramisetti,
  • Preeti Bhadauria,
  • Jacob Schick,
  • Zheng Zeng,
  • Varun Sharma,
  • Wendy Dunton,
  • Sinisa Dovat,
  • Dhimant Desai,
  • Dhimant Desai,
  • Hong Zheng,
  • Hong Zheng,
  • David J. Feith,
  • David J. Feith,
  • Thomas P. Loughran,
  • Thomas P. Loughran,
  • Shantu Amin,
  • Shantu Amin,
  • Arun K. Sharma,
  • Arun K. Sharma,
  • David Claxton,
  • David Claxton,
  • Arati Sharma,
  • Arati Sharma,
  • Arati Sharma

DOI
https://doi.org/10.3389/fonc.2020.00393
Journal volume & issue
Vol. 10

Abstract

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Acute myeloid leukemia is a heterogeneous disease with a 5-year survival rate of 28.3%, and current treatment options constrained by dose-limiting toxicities. One of the key signaling pathways known to be frequently activated and dysregulated in AML is PI3K/AKT. Its dysregulation is associated with aggressive cell growth and drug resistance. We investigated the activity of Phenybutyl isoselenocyanate (ISC-4) in primary cells obtained from newly diagnosed AML patients, diverse AML cell lines, and normal cord blood cells. ISC-4 significantly inhibited survival and clonogenicity of primary human AML cells without affecting normal cells. We demonstrated that ISC-4-mediated p-Akt inhibition caused apoptosis in primary AML (CD34+) stem cells and enhanced efficacy of cytarabine. ISC-4 impeded leukemia progression with improved overall survival in a syngeneic C1498 mouse model with no obvious toxic effects on normal myelopoiesis. In U937 xenograft model, bone marrow cells exhibited significant reduction in human CD45+ cells in ISC-4 (~87%) or AraC (~89%) monotherapy groups compared to control. Notably, combination treatment suppressed the leukemic infiltration significantly higher than the single-drug treatments (~94%). Together, the present findings suggest that ISC-4 might be a promising agent for AML treatment.

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