Hsp90 inhibitor NVP-AUY922 enhances radiation sensitivity of tumor cell lines under hypoxia

• Published in: Cancer biology & therapy 2012-04, Vol.13 (6), p.425-434
• Main Authors: Djuzenova, Cholpon S., Blassl, Christina, Roloff, Konstanze, Kuger, Sebastian, Katzer, Astrid, Niewidok, Natalia, Günther, Nadine, Polat, Bülent, Sukhorukov, Vladimir L., Flentje, Michael
• Format: Article
• Language: English
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma - radiotherapy; CDC2 Protein Kinase - metabolism; Cell; Cell Cycle - drug effects; cell cycle arrest; Cell Hypoxia; Cell Line, Tumor; colony survival; Cycle; Cyclin-Dependent Kinase 4 - metabolism; DNA damage; DNA Damage - drug effects; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - radiotherapy; histone γH2AX; Histones - metabolism; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Isoxazoles - pharmacology; Landes; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Organogenesis; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Radiation, Ionizing; Radiation-Sensitizing Agents - pharmacology; reoxygenation; Resorcinols - pharmacology
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.19294

NVP-AUY922, a novel inhibitor of Hsp90, was shown to enhance the effect of ionizing radiation (IR) on tumor cells under normoxic conditions. Since low oxygen tension is a common feature of solid tumors, we explore in the present study the impact of hypoxia on the combined treatment of lung carcinoma A549 and glioblastoma SNB19 cell lines with NVP-AUY922 and IR. Cellular analysis included the colony-forming ability, expression of CAIX, Hsp90, Hsp70, Raf-1, Akt, cell cycle progression and associated proteins, as well as DNA damage measured by histone γH2AX.   The clonogenic assay revealed that in both cell lines NVP-AUY922 enhanced the radiotoxicity under hypoxic exposure to a level similar to that observed under oxic conditions. Irrespective of oxygen supply during drug treatment, NVP-AUY922 also reduced the expression of anti-apoptotic proteins Raf-1 and Akt. As judged by the levels of histone γH2AX, drug-treated hypoxic cells exhibited a lower repair rate of DNA double-strand breaks than normoxic cells. The drug-IR mediated changes in the cell cycle, i.e., S-phase depletion and G 2 /M arrest, developed not directly during hypoxic exposure but first upon 24 h reoxygenation. Under both oxygen tensions, Hsp90 inhibition downregulated the cell cycle-associated proteins, Cdk1, Cdk4 and pRb. The finding that NVP-AUY922 can enhance the in vitro radiosensitivity of hypoxic tumor cells may have implications for the combined modality treatment of solid tumors.