The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

Cancers

Roberto Gomez-Casal³  Chitralekha Bhattacharya³  Michael W. Epperly³  Per H. Basse³  Hong Wang³  Xinhui Wang²  David A. Proia¹  Joel S. Greenberger³  Mark A. Socinski³  Vera Levina³ 

[1] Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA; E-Mail:;Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115, USA; E-Mail:;The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA; E-Mails:

关键词: HSP90 inhibitor ganetespib;    lung adenocarcinoma;    xenografted tumors;    ionizing radiation;    senescence;    apoptosis;    cell cycle;    DNA repair;   

DOI  :  10.3390/cancers7020814

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.