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Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress
- Source :
- Bone Marrow Research, Bone Marrow Research, Vol 2012 (2012)
- Publication Year :
- 2012
- Publisher :
- Hindawi Publishing Corporation, 2012.
-
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.
- Subjects :
- Valproic Acid
Article Subject
lcsh:RC633-647.5
Immunology
RPTOR
Retinoic acid
Myeloid leukemia
Cell Biology
Hematology
lcsh:Diseases of the blood and blood-forming organs
Pharmacology
Biology
In vitro
chemistry.chemical_compound
chemistry
Cell culture
Apoptosis
medicine
PI3K/AKT/mTOR pathway
medicine.drug
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 20903006 and 20902999
- Volume :
- 2012
- Database :
- OpenAIRE
- Journal :
- Bone Marrow Research
- Accession number :
- edsair.doi.dedup.....fb701a341966e47e4ad1de322ca341bc