Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress
Open Access
- 2 October 2012
- journal article
- research article
- Published by Hindawi Limited in Bone Marrow Research
- Vol. 2012, 1-10
- https://doi.org/10.1155/2012/329061
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.Keywords
Funding Information
- Norwegian Cancer Society
This publication has 34 references indexed in Scilit:
- Inhibition of the mTORC2 and chaperone pathways to treat leukemiaBlood, 2012
- Autophagy Activation: A Novel Mechanism of Atorvastatin to Protect Mesenchymal Stem Cells from Hypoxia and Serum Deprivation via AMP-Activated Protein Kinase/Mammalian Target of Rapamycin PathwayStem Cells and Development, 2012
- Single-Cell Pharmacodynamic Monitoring of S6 Ribosomal Protein Phosphorylation in AML Blasts during a Clinical Trial Combining the mTOR Inhibitor Sirolimus and Intensive ChemotherapyClinical Cancer Research, 2012
- NF-kappaB P50/P65 hetero-dimer mediates differential regulation of CD166/ALCAM expression via interaction with micoRNA-9 after serum deprivation, providing evidence for a novel negative auto-regulatory loopNucleic Acids Research, 2011
- Current and future directions in mammalian target of rapamycin inhibitors developmentExpert Opinion on Investigational Drugs, 2011
- New inhibitors of the mammalian target of rapamycin signaling pathway for cancerExpert Opinion on Investigational Drugs, 2010
- Targeted therapy in acute myeloid leukaemia: current status and future directionsExpert Opinion on Investigational Drugs, 2009
- Nuclear Factor-κB Signaling: A Contributor in Leukemogenesis and a Target for Pharmacological Intervention in Human Acute Myelogenous LeukemiaCritical Reviews™ in Oncogenesis, 2009
- Activation ofPrn-p gene and stable transfection ofPrn-p cDNA in leukemia MEL and neuroblastoma N2a cells increased production of PrPC but not prevented DNA fragmentation initiated by serum deprivationJournal of Cellular Physiology, 2006
- Combination Mammalian Target of Rapamycin Inhibitor Rapamycin and HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Has Synergistic Activity in Multiple MyelomaClinical Cancer Research, 2006