Table of Contents
Bone Marrow Research
Volume 2012, Article ID 329061, 10 pages
http://dx.doi.org/10.1155/2012/329061
Research Article

Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress

1Division of Hematology, Institute of Medicine, University of Bergen, N-5021 Bergen, Norway
2Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway

Received 25 May 2012; Revised 3 August 2012; Accepted 27 August 2012

Academic Editor: Guido Kobbe

Copyright © 2012 Anita Ryningen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Effects of the mTOR inhibitor rapamycin were characterized on in vitro cultured primary human acute myeloid leukemia (AML) cells and five AML cell lines. Constitutive mTOR activation seemed to be a general characteristic of primary AML cells. Increased cellular stress induced by serum deprivation increased both mTOR signaling, lysosomal acidity, and in vitro apoptosis, where lysosomal acidity/apoptosis were independent of increased mTOR signaling. Rapamycin had antiproliferative and proapoptotic effects only for a subset of patients. Proapoptotic effect was detected for AML cell lines only in the presence of serum. Combination of rapamycin with valproic acid, all-trans retinoic acid (ATRA), and NF-κB inhibitors showed no interference with constitutive mTOR activation and mTOR inhibitory effect of rapamycin and no additional proapoptotic effect compared to rapamycin alone. In contrast, dual inhibition of the PI3K-Akt-mTOR pathway by rapamycin plus a PI3K inhibitor induced new functional effects that did not simply reflect a summary of single drug effects. To conclude, (i) pharmacological characterization of PI3K-Akt-mTOR inhibitors requires carefully standardized experimental models, (ii) rapamycin effects differ between patients, and (iii) combined targeting of different steps in this pathway should be further investigated whereas combination of rapamycin with valproic acid, ATRA, or NF-κB inhibitors seems less promising.