The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells
| Autor: | Hong Wang, Roberto Gomez-Casal, David A. Proia, Per H. Basse, Xinhui Wang, Mark A. Socinski, Chitralekha Bhattacharya, Joel S. Greenberger, Michael W. Epperly, Vera Levina |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
senescence DNA repair Ganetespib Biology HSP90 inhibitor ganetespib lung adenocarcinoma xenografted tumors ionizing radiation apoptosis cell cycle lcsh:RC254-282 Article Hsp90 inhibitor In vivo PI3K/AKT/mTOR pathway Cell cycle lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Hsp90 3. Good health Oncology Apoptosis Cancer research biology.protein |
| Zdroj: | Cancers, Vol 7, Iss 2, Pp 876-907 (2015) Cancers; Volume 7; Issue 2; Pages: 876-907 Cancers Volume 7 Issue 2 Pages 876-907 |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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