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Cancers 2015, 7(2), 876-907; doi:10.3390/cancers7020814

The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

1
The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA
2
Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213, USA
3
Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213, USA
4
Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15213, USA
5
Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA 15213, USA
6
Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115, USA
7
Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA
Current address: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Rm. 1.19c, 5117 Center Ave., Pittsburgh, PA 15213, USA.
*
Author to whom correspondence should be addressed.
Academic Editor: Robert H. Weiss
Received: 6 March 2015 / Accepted: 12 May 2015 / Published: 22 May 2015
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Abstract

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. View Full-Text
Keywords: HSP90 inhibitor ganetespib; lung adenocarcinoma; xenografted tumors; ionizing radiation; senescence; apoptosis; cell cycle; DNA repair HSP90 inhibitor ganetespib; lung adenocarcinoma; xenografted tumors; ionizing radiation; senescence; apoptosis; cell cycle; DNA repair
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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. (CC BY 4.0).

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MDPI and ACS Style

Gomez-Casal, R.; Bhattacharya, C.; Epperly, M.W.; Basse, P.H.; Wang, H.; Wang, X.; Proia, D.A.; Greenberger, J.S.; Socinski, M.A.; Levina, V. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells. Cancers 2015, 7, 876-907.

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