Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction

• DOI: 10.1038/sj.bjc.6605683
• Publication Date: 2010-05-26T08:22:11Z
• Authors: L Stingl; T Stühmer; M Chatterjee; M R Jensen; M Flentje; C S Djuzenova
• Keywords: Radiosensitivity; Radioresistance; Comet Assay

Heat-shock protein 90 (Hsp90) has a crucial role in both the stabilisation and regulation of various proteins, including those related to radioresistance. Inhibition Hsp90 may therefore provide strategy for enhancing radiosensitivity tumour cells. This study explores responses four cell lines (A549, GaMG, HT 1080 SNB19) combined treatment with ionising radiation (IR) two novel inhibitors Hsp90, NVP-AUY922 NVP-BEP800. The techniques used included colony counts, expression Hsp70, Akt, survivin, cleaved caspase 3, p53, cell-cycle progression associated proteins. DNA damage was analysed by histone γH2AX Comet assays. We found that NVP-BEP800 enhanced all tested lines. In contrast, only (HT GaMG) exhibited an increased rate apoptosis after drug pretreatment, as revealed western blot. lines, γH2AX, marker double-strand breaks, drug-IR higher its decay slower than each single modality. Drug-IR also resulted impaired progression, indicated S-phase depletion G2/M arrest. addition, cycle-associated Cdk1 Cdk4, were downregulated inhibition. These findings show can radiosensitise different entities through destabilisation several client thus causing S phase arrest, repair protraction and, some extent, apoptosis. results might have important implications radiotherapy solid tumours.