%0 Journal Article
%T Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress
%A Anita Ryningen
%A Hˋkon Reikvam
%A Ina Nepstad
%A Kristin Paulsen Rye
%A ˋystein Bruserud
%J Bone Marrow Research
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/329061
%X 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-百B 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-百B inhibitors seems less promising. 1. Introduction Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by bone marrow infiltration of immature leukemic myeloblasts, and the overall disease-free survival is only 40每50% even for the younger patients below 60每65 years of age who receive the most intensive chemotherapy [1, 2]. New therapeutic approaches are thus warranted [3], and inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway may become a future strategy because this pathway is constitutively activated in the leukemia cells for most patients and seems important for regulation of cell proliferation, viability, and autophagy [4每8]. However, despite these observations the initial clinical studies showed an antileukemic effect of mTOR inhibition only for a subset of patients [9]. Thus, the future development and optimal use of PI3K-Akt-mTOR inhibition as a therapeutic strategy in human AML will probably depend on a more detailed functional characterization of this pathway using standardized in vitro models [4每7]. 2. Material and Methods 2.1. Pharmacological Agents The first generation mTOR inhibitor
%U http://www.hindawi.com/journals/bmr/2012/329061/