mTORC1/2 Inhibitor Served as a More Ideal Agent Against the Growth of Mouse Lymphocytic Leukemia Both In Vitro and In Vivo

Anticancer Res. 2019 Sep;39(9):4829-4835. doi: 10.21873/anticanres.13668.

Abstract

Background/aim: Chronic lymphocytic leukemia (CLL) still remains an incurable disease as the cells evade apoptosis, which is an obstacle for current therapeutic approaches. Therefore, our aim was to identify an ideal target of leukemic cell growth for developing inhibitors.

Materials and methods: Mouse lymphocytic leukemia cell line L1210, human Toledo cells and a DBA/2 mouse graft model were used to analyze the activity of dual mTORC1/2 inhibitor AZD2014s. Western blotting and flow cytometry were performed to determine the mechanism.

Results: AZD2014 inhibited L1210 and human Toledo cell proliferation. Treatment with AZD2014 reduced the phosphorylation levels of S6K1 and 4EBP1 and the protein levels of Rictor, a component of the mTORC2 pathway. AZD2014 induced cell cycle arrest at the G0-G1 phase by reducing the expression of cyclin D1 and CDK4. Oral administration of AZD2014 significantly inhibited the growth of L1210 cell grafts in DBA/2 mice.

Conclusion: The mTORC1/2 inhibitor may be a better therapeutic agent compared to PI3K/mTORC1 inhibitors for treating patients with CLL.

Keywords: AZD2014; Chronic lymphocytic leukemia; mTORC1/2; mammalian target of rapamycin.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Humans
  • Leukemia, Lymphoid / drug therapy
  • Leukemia, Lymphoid / metabolism
  • Leukemia, Lymphoid / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors*
  • Mice
  • Morpholines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines

Substances

  • Antineoplastic Agents
  • Benzamides
  • Morpholines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • vistusertib
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2