Targeting of mTOR in AML Is Associated with Decreased Growth of Leukemic Cells and Downregulation of VEGF.

The mammalian target of rapamycin (mTOR), a key-regulator of cell cycle progression, has recently been implicated in growth of neoplastic cells and tumor- and leukemia-associated angiogenesis. In addition, mTOR has been described as a regulator of expression of vascular endothelial growth factor (VEGF), a cytokine involved in tumor-related angiogenesis, in various neoplasms. We asked whether mTOR can be employed as a new therapeutic target in acute myeloid leukemia (AML) using the mTOR-targeting drug rapamycin and its derivatives RAD001 (everolimus) and CCI-779. As assessed by ³H-thymidine incorporation, rapamycin was found to counteract growth of AML cells in vitro in 9/11 patients examined as well as in the AML-derived cell lines U937, HL60, and KG1a. The effects of rapamycin on growth of AML cells were dose-dependent (primary AML cells: IC₅₀: 10 pM - 1 nM; inhibition of ³H-thymidine uptake at 1 nM of rapamycin: 43±15 % of control; p<0.05) and associated with G1 cell cycle arrest as well as apoptosis. The same results were obtained with RAD001 and CCI-779. In all responsive cells analyzed, rapamycin and its derivatives decreased expression of VEGF in AML cells at the mRNA- and protein level. Exogenously added VEGF was found to revert the rapamycin-induced inhibition of growth in HL60 cells, but did not revert rapamycin effects in KG1a cells, U937 cells, or primary AML cells. In summary, our data suggest that rapamycin and its derivatives act antileukemic in AML cells by two distinct mechanisms, namely direct inhibition of cell growth and suppression of proangiogenic VEGF. mTOR may be a new interesting target in AML.