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

Djuzenova, Cholpon S.; Blassl, Christina; Roloff, Konstanze; Kuger, Sebastian; Katzer, Astrid; Niewidok, Natalia; Günther, N.; Polat, Bülent; Sukhorukov, Vladimir L.; Flentje, Michael

doi:10.4161/cbt.19294

Cited by 21 publications

(8 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For HSP90i and CCRT in bladder cancer, mechanistic studies focused on HER2 and AKT signalling with no investigation of the impact of HSP90i on DDR signalling [ 25 ]. Likewise studies into sensitization to radiation or cisplatin alone often focused on cell cycle, growth and apoptotic signalling pathways [ 22 , 24 , 32 , 34 – 36 ]. Choi et al identified HSP90i by bioinformatics as a means to convert HR proficient to HR deficient tumours [ 23 ] but DDR analysis was restricted to γH2Ax and RAD51 foci formation as has been the case in other studies [ 17 , 22 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation

et al. 2017

View full text Add to dashboard Cite

BackgroundConcurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT.MethodsThe ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo.ResultsThe combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function.ConclusionsThis study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials.

show abstract

Section: Discussionmentioning

confidence: 99%

HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…As Hsp90 inhibitor is known to affect the cell cycle checkpoint [23][24][25][26][27][28][29]32], we also studied cell cycle effects after various combinations of treatment with 17AAG and radiation. Figure 7 shows our cell cycle data.…”

Section: G2 Delay Induced By Carbon Irradiation Is Further Intensifiementioning

confidence: 99%

“…The combination of Hsp90 inhibitor and radiation on tumor cells has been studied and enhancement of radiation effect with the inhibitors has been well documented [18][19][20][21][22][23][24][25][26][27][28][29][30]. Hypoxic tumor cells were also radiosensitized by the combination strategy [31,32]. Some of these studies indicated that, as compared with tumor cells, normal cells might not be affected, indicating a selective radiosensitization of tumor cells [18,19,21].…”

Section: Introductionmentioning

confidence: 99%

“…We and others have also shown that one of the causes of sensitization could be inhibition of DNA double strand break (DSB) repair [21][22][23][25][26][27]. Checkpoint arrest mainly at G2/M phase has also been suggested as a cause of radiosensitization with Hsp90 inhibitors [23][24][25][26][27][28][29]32]. An interesting study recently reported that Hsp90 inhibitor 17AAG induces BRCA1 ubiquitination and proteasomal degradation, leading to repair inhibition of DSBs induced by ionizing radiation [33].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The combination of Hsp90 inhibitor 17AAG and heavy‐ion irradiation provides effective tumor control in human lung cancer cells

Hirakawa¹,

Fujisawa

Masaoka³

et al. 2015

Cancer Medicine

View full text Add to dashboard Cite

Hsp90 inhibitors have become well-studied antitumor agents for their selective property against tumors versus normal cells. The combined treatment of Hsp90 inhibitor and conventional photon radiation also showed more effective tumor growth delay than radiation alone. However, little is known regarding the combined treatment of Hsp90 inhibitor and heavy-ion irradiation. In this study, SQ5 human lung tumor cells were used in vitro for clonogenic cell survival and in vivo for tumor growth delay measurement using a mouse xenograft model after 17-allylamino-17-demethoxygeldanamycin (17AAG) pretreatment and carbon ion irradiation. Repair of DNA double strand breaks (DSBs) was also assessed along with expressions of DSB repair-related proteins. Cell cycle analysis after the combined treatment was also performed. The combined treatment of 17AAG and carbon ions revealed a promising treatment option in both in vitro and in vivo studies. One likely cause of this effectiveness was shown to be the inhibition of homologous recombination repair by 17AAG. The more intensified G2 cell cycle delay was also associated with the combined treatment when compared with carbon ion treatment alone. Our findings indicate that the combination of Hsp90 inhibition and heavy-ion irradiation provides a new effective therapeutic alternative for treatment of solid tumors.

show abstract

“…Recenly, inhibitors of hsp90 with improved bioavailability and lower toxicity have become available, including a series of pyrazole resorcinol compounds that have proven to be stronger inhibitors of hsp90 (NVP-AUY922) 120 . Treatment of cancer cells, including NSCLC, with NVP-AUY922 leads to radiosensitization under normoxic and hypoxic condition 121,122 . The radiosensitization was accompanied by effects on DNA repair, cell cycle progression 123 and abrogation of homologous recombination leading to mitotic entry with unresolved DNA damage 124 .…”

Section: Heat Shock Protein 90mentioning

confidence: 99%

Membrane Phospholipids, EML4-ALK, and Hsp90 as Novel Targets in Lung Cancer Treatment

Laszlo¹,

Thotala²,

Hallahan³

2013

The Cancer Journal

View full text Add to dashboard Cite

Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease; combined cytotoxic chemotherapy and radiation therapy delivered concurrently has been established as the standard treatment for such patients. Despite many clinical trials testing many different radiochemotherapy combinations, it seems that a plateau of efficiencies at the acceptable risk of complications has been reached. Clinical studies indicate that the improved efficacy of radiochemotherapy is associated with the radiosensitizing effects of chemotherapy. Improvement of outcomes of this combined modality by developing novel radiosensitisers is a viable therapeutic strategy. In addition to causing cell death, ionizing radiation also induces a many-faceted signaling response, which activates many pro-survival pathways leading to enhanced proliferation in the surviving fraction of cells and increased vascularization in tumors. Radiation at doses used in the clinic activates cytoplasmic phospholipase A2 (cPLA2), leading to increased production of arachidonic acid (AA) and lysophosphatidylcholine (LPC). The former is the initial step in the generation of eicosanoids, while the later is the initial step in the formation of lysophosphaditic acid, leading to the activation of inflammatory pathways. The echinoderm microtubule associated protein-like 4 Anaplastic lymphoma kinase (EML4-ALK) is member of the insulin superfamily of receptor tyrosine kinases. The EML4-ALK fusion gene appears unique to lung cancer and signals through Erk and PI3K. Heat shock protein 90 (Hsp90) is often overexpressed and present in an activated multichaperone complex in cancer cells and it is now regarded as essential for malignant transformation and progression. In this review we focus on radiosensitizing strategies involving the targeting of membrane phospholipids, EML4-ALK and Hsp90 with specific inhibitors.

show abstract

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

Cited by 21 publications

References 44 publications

HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation

HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation

The combination of Hsp90 inhibitor 17AAG and heavy‐ion irradiation provides effective tumor control in human lung cancer cells

Membrane Phospholipids, EML4-ALK, and Hsp90 as Novel Targets in Lung Cancer Treatment

Contact Info

Product

Resources

About