The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells
The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibito...
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| Format: | Article |
| Language: | English |
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MDPI AG
2015-05-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/7/2/0814 |
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| author | Roberto Gomez-Casal Chitralekha Bhattacharya Michael W. Epperly Per H. Basse Hong Wang Xinhui Wang David A. Proia Joel S. Greenberger Mark A. Socinski Vera Levina |
| author_facet | Roberto Gomez-Casal Chitralekha Bhattacharya Michael W. Epperly Per H. Basse Hong Wang Xinhui Wang David A. Proia Joel S. Greenberger Mark A. Socinski Vera Levina |
| author_sort | Roberto Gomez-Casal |
| collection | DOAJ |
| description | The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors. |
| first_indexed | 2024-03-12T06:41:33Z |
| format | Article |
| id | doaj.art-d966e2c353c84e9cabfc54a6cead9e4f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:41:33Z |
| publishDate | 2015-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d966e2c353c84e9cabfc54a6cead9e4f2023-09-03T00:59:38ZengMDPI AGCancers2072-66942015-05-017287690710.3390/cancers7020814cancers7020814The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma CellsRoberto Gomez-Casal0Chitralekha Bhattacharya1Michael W. Epperly2Per H. Basse3Hong Wang4Xinhui Wang5David A. Proia6Joel S. Greenberger7Mark A. Socinski8Vera Levina9The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAHarvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115, USASynta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USAThe molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.http://www.mdpi.com/2072-6694/7/2/0814HSP90 inhibitor ganetespiblung adenocarcinomaxenografted tumorsionizing radiationsenescenceapoptosiscell cycleDNA repair |
| spellingShingle | Roberto Gomez-Casal Chitralekha Bhattacharya Michael W. Epperly Per H. Basse Hong Wang Xinhui Wang David A. Proia Joel S. Greenberger Mark A. Socinski Vera Levina The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells Cancers HSP90 inhibitor ganetespib lung adenocarcinoma xenografted tumors ionizing radiation senescence apoptosis cell cycle DNA repair |
| title | The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells |
| title_full | The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells |
| title_fullStr | The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells |
| title_full_unstemmed | The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells |
| title_short | The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells |
| title_sort | hsp90 inhibitor ganetespib radiosensitizes human lung adenocarcinoma cells |
| topic | HSP90 inhibitor ganetespib lung adenocarcinoma xenografted tumors ionizing radiation senescence apoptosis cell cycle DNA repair |
| url | http://www.mdpi.com/2072-6694/7/2/0814 |
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