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

Abstract

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.

• Authors: Cholpon S Djuzenova, Christina Blassl, Konstanze Roloff, Sebastian Kuger, Astrid Katzer, Natalia Niewidok, Nadine Günther, Bülent Polat, Vladimir L Sukhorukov, Michael Flentje
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 13 Issue 6 Pg. 425-34 (Apr 2012) ISSN: 1555-8576 [Electronic] United States
• PMID: 22286776 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• H2AX protein, human
• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Histones
• Isoxazoles
• Radiation-Sensitizing Agents
• Resorcinols
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-raf
• CDC2 Protein Kinase
• CDK4 protein, human
• Cyclin-Dependent Kinase 4

Topics

• CDC2 Protein Kinase (metabolism)
• Carcinoma (drug therapy, metabolism, pathology, radiotherapy)
• Cell Cycle (drug effects)
• Cell Hypoxia
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4 (metabolism)
• DNA Damage (drug effects)
• Glioblastoma (drug therapy, metabolism, pathology, radiotherapy)
• HSP70 Heat-Shock Proteins (metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Histones (metabolism)
• Humans
• Isoxazoles (pharmacology)
• Lung Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Radiation, Ionizing
• Radiation-Sensitizing Agents (pharmacology)
• Resorcinols (pharmacology)