Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity1
The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the...
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Published in | Translational oncology Vol. 6; no. 3; pp. 355 - 362 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Neoplasia Press Inc
01.06.2013
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Online Access | Get full text |
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Abstract | The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the competitive mTOR inhibitor PP242. On the basis of immunoblot analyses, whereas rapamycin only partially inhibited mTOR complex 1 (mTORC1) activity and had no effect on mTOR complex 2 (mTORC2), PP242 inhibited the activity of both mTOR-containing complexes. Irradiation alone had no effect on mTORC1 or mTORC2 activity. Clonogenic survival was used to define the effects of the mTOR inhibitors on
in vitro
radiosensitivity. In the two tumor cell lines evaluated, PP242 treatment 1 hour before irradiation increased radiosensitivity, whereas rapamycin had no effect. Addition of PP242 after irradiation also enhanced the radiosensitivity of both tumor lines. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated according γH2AX foci. PP242 exposure did not influence the initial level of γH2AX foci after irradiation but did significantly delay the dispersal of radiation-induced γH2AX foci. In contrast to the tumor cell lines, the radiosensitivity of a normal human fibroblast cell line was not influenced by PP242. Finally, PP242 administration to mice bearing U251 xenografts enhanced radiation-induced tumor growth delay. These results indicate that in a preclinical tumor model PP242 enhances tumor cell radiosensitivity both
in vitro
and
in vivo
and suggest that this effect involves an inhibition of DNA repair. |
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AbstractList | The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the competitive mTOR inhibitor PP242. On the basis of immunoblot analyses, whereas rapamycin only partially inhibited mTOR complex 1 (mTORC1) activity and had no effect on mTOR complex 2 (mTORC2), PP242 inhibited the activity of both mTOR-containing complexes. Irradiation alone had no effect on mTORC1 or mTORC2 activity. Clonogenic survival was used to define the effects of the mTOR inhibitors on
in vitro
radiosensitivity. In the two tumor cell lines evaluated, PP242 treatment 1 hour before irradiation increased radiosensitivity, whereas rapamycin had no effect. Addition of PP242 after irradiation also enhanced the radiosensitivity of both tumor lines. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated according γH2AX foci. PP242 exposure did not influence the initial level of γH2AX foci after irradiation but did significantly delay the dispersal of radiation-induced γH2AX foci. In contrast to the tumor cell lines, the radiosensitivity of a normal human fibroblast cell line was not influenced by PP242. Finally, PP242 administration to mice bearing U251 xenografts enhanced radiation-induced tumor growth delay. These results indicate that in a preclinical tumor model PP242 enhances tumor cell radiosensitivity both
in vitro
and
in vivo
and suggest that this effect involves an inhibition of DNA repair. |
Author | Hayman, Thomas J Kahn, Jenna Jamal, Muhammad Kramp, Tamalee Camphausen, Kevin Tofilon, Philip J |
AuthorAffiliation | University of South Florida Morsani College of Medicine, Tampa, FL Warren Alpert School of Medicine, Brown University, Providence, RI Radiation Oncology Branch, National Cancer Institute, Bethesda, MD |
AuthorAffiliation_xml | – name: Radiation Oncology Branch, National Cancer Institute, Bethesda, MD – name: Warren Alpert School of Medicine, Brown University, Providence, RI – name: University of South Florida Morsani College of Medicine, Tampa, FL |
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Title | Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity1 |
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