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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
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 in...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467767/ https://www.ncbi.nlm.nih.gov/pubmed/23082251 http://dx.doi.org/10.1155/2012/329061 |
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author | Ryningen, Anita Reikvam, Håkon Nepstad, Ina Paulsen Rye, Kristin Bruserud, Øystein |
author_facet | Ryningen, Anita Reikvam, Håkon Nepstad, Ina Paulsen Rye, Kristin Bruserud, Øystein |
author_sort | Ryningen, Anita |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3467767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-34677672012-10-18 Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress Ryningen, Anita Reikvam, Håkon Nepstad, Ina Paulsen Rye, Kristin Bruserud, Øystein Bone Marrow Res Research Article 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. Hindawi Publishing Corporation 2012 2012-10-02 /pmc/articles/PMC3467767/ /pubmed/23082251 http://dx.doi.org/10.1155/2012/329061 Text en Copyright © 2012 Anita Ryningen et al. https://creativecommons.org/licenses/by/3.0/ 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. |
spellingShingle | Research Article Ryningen, Anita Reikvam, Håkon Nepstad, Ina Paulsen Rye, Kristin Bruserud, Øystein Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress |
title | Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress |
title_full | Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress |
title_fullStr | Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress |
title_full_unstemmed | Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress |
title_short | Inhibition of Mammalian Target of Rapamycin in Human Acute Myeloid Leukemia Cells Has Diverse Effects That Depend on the Environmental In Vitro Stress |
title_sort | inhibition of mammalian target of rapamycin in human acute myeloid leukemia cells has diverse effects that depend on the environmental in vitro stress |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467767/ https://www.ncbi.nlm.nih.gov/pubmed/23082251 http://dx.doi.org/10.1155/2012/329061 |
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