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mTOR regulates cell survival after etoposide treatment in primary AML cells

Qing Xu1, James E Thompson, Martin Carroll

  • 1Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Blood
|September 10, 2005
PubMed

Insights

This study reveals that inhibiting mTOR with rapamycin enhances etoposide chemotherapy's effectiveness against acute myeloid leukemia (AML) cells and stem cells. Combining rapamycin with etoposide shows promise for treating AML.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Acute myeloid leukemia (AML) cells exhibit constitutive activation of the phosphatidylinositol 3(PI3) kinase pathway, crucial for their survival.
  • The precise role of the PI3K pathway, particularly its substrate mTOR (mammalian target of rapamycin), in leukemic cell survival remains incompletely understood.

Purpose of the Study:

  • To investigate the role of mTOR in the survival of primary acute myeloid leukemia cells.
  • To evaluate the efficacy of inhibiting mTOR with rapamycin, alone and in combination with etoposide, in AML treatment models.

Main Methods:

  • Development of a novel growth medium to improve the survival of AML blasts and leukemic stem cells in culture.
  • Treatment of AML cells with rapamycin, etoposide, or a combination thereof.
  • Assessment of cell survival and cytotoxicity using long-term suspension cultures.
  • Evaluation of the effect on AML stem cell engraftment in nonobese diabetic/severe combined immunodeficient (NOD/SCID) animal models.

Main Results:

  • Rapamycin alone induced a modest decrease in AML cell survival over time.
  • The combination of rapamycin and etoposide significantly increased the cytotoxicity of etoposide against AML blasts.
  • Etoposide reduced AML cell engraftment in vivo, an effect potentiated by rapamycin, indicating mTOR's role in AML stem cell survival post-treatment.

Conclusions:

  • mTOR signaling is critical for the survival of AML stem cells, especially after chemotherapy exposure.
  • Combining rapamycin with etoposide-based chemotherapy may represent a novel and effective therapeutic strategy for acute myeloid leukemia.

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