[The Mechanism of Combination using mTORC1/2 Inhibitor and Imatinib to Suppress Cell Proliferation of Ph +ALL Cell Line]

Sichuan Da Xue Xue Bao Yi Xue Ban. 2017 Mar;48(2):216-220.
[Article in Chinese]

Abstract

Objectives: To investigate the anti-leukemia effect and mechanism of mTORC1/2 inhibitor PP242 combined with imatinib (IM) on the proliferation of Ph+ acute lymphoblastic leukemia (ALL) cell line SUP-B15.

Methods: SUP-B15 cell line was treated with PP242, imatinib (IM), or PP242 plus IM for 72 h, IC50 values (the concentration of drug required to kill 50% of the cells) and the combination index (CI ) of synergistic cytotoxicity was determined using MTT methods. The expressions of PI3K/Akt/mTOR and apoptosis associated proteins were examined by Western blot test.

Results: The IC50 value of IM alone was (1.50±0.09) μmol/L, however, the IC50 values were (0.81±0.030) μmol/L, (0.36±0.140) μmol/L and (0.02±0.002) μmol/L combined with 20 nmol/L, 30 nmol/L and 50 nmol/L of PP242, and the CI values were 0.764, 0.545 and 0.507, indicating two drugs had highly synergistic effect on anti-proliferation in the SUP-B15 cell line. The expressions of p-Akt, p-4EBP1, p-elF4E, p-cAbl, p-mTOR and p-P70 were down-regulated significantly in a dose-dependent and time-dependent manner after PP242 treatment#.Compared with PP242 or IM alone, the down-regulation of PI3K/Akt/mTOR signaling pathway and the up-regulation of the apoptosis associated proteins (bax and cleaved caspase-3) were more significant in the combination of two drugs.

Conclusion: The combination of IM and PP242 could increase the inhibition of PI3K/Akt/mTOR signaling pathway and apoptosis mediated by bax and caspase-3 in SUP-B15 cell line.

Keywords: Akt; Imatinib; PP242; Ph⁺ acute lymphoblastic leukemia; mTORC1/2.

MeSH terms

  • Apoptosis
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Humans
  • Imatinib Mesylate / pharmacology*
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • bcl-2-Associated X Protein / metabolism

Substances

  • BAX protein, human
  • bcl-2-Associated X Protein
  • Imatinib Mesylate
  • Phosphatidylinositol 3-Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • CASP3 protein, human
  • Caspase 3