Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation

Machida, Hikaru; Matsumoto, Yoshitaka; Shirai, Makoto; Kubota, Nobuo

doi:10.1080/09553000310001626135

Cited by 74 publications

(55 citation statements)

References 19 publications

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“…Previous studies have shown that inhibition of Hsp90 enhances the radiation response of several cell lines derived from a variety of human tumour entities (Bisht et al, 2003;Enmon et al, 2003;Machida et al, 2003;Russell et al, 2003;Bull et al, 2004;Harashima et al, 2005;Dote et al, 2006). These findings validate the molecular chaperone Hsp90 as a clinically relevant target for tumour radiosensitisation.…”

Section: Discussionsupporting

confidence: 60%

“…Indeed, a number of studies have already explored Hsp90 as a potential molecular target for radiosensitisation of tumour cells (Bisht et al, 2003;Machida et al, 2003;Russell et al, 2003;Bull et al, 2004;Harashima et al, 2005;Dote et al, 2006;Kabakov et al, 2008;Wu et al, 2009). Thus, the inhibitor of Hsp90, geldanamycin, and its derivatives significantly enhance the radiosensitivity of tumour cell lines derived from a variety of histologies, including glioma, prostate, pancreas and cervix (Bisht et al, 2003;Enmon et al, 2003;Machida et al, 2003;Russell et al, 2003;Bull et al, 2004;Harashima et al, 2005;Dote et al, 2006). However, geldanamycins have several limitations, including poor solubility, formulation difficulties, hepatotoxicity and extensive metabolism by polymorphic enzymes, along with drug efflux by P-glycoprotein (Kelland et al, 1999;Eiseman et al, 2005;Brough et al, 2008;Eccles et al, 2008).…”

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confidence: 99%

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

et al. 2010

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BACKGROUND: Heat-shock protein 90 (Hsp90) has a crucial role in both the stabilisation and regulation of various proteins, including those related to radioresistance. Inhibition of Hsp90 may therefore provide a strategy for enhancing the radiosensitivity of tumour cells. This study explores the responses of four tumour cell lines (A549, GaMG, HT 1080 and SNB19) to combined treatment with ionising radiation (IR) and two novel inhibitors of Hsp90, NVP-AUY922 and NVP-BEP800. The techniques used included cell and colony counts, expression of Hsp90, Hsp70, Akt, survivin, cleaved caspase 3, p53, cell-cycle progression and associated proteins. DNA damage was analysed by histone gH2AX and Comet assays. RESULTS: We found that NVP-AUY922 and NVP-BEP800 enhanced radiosensitivity in all tested cell lines. In contrast, only two cell lines (HT 1080 and GaMG) exhibited an increased rate of apoptosis after drug pretreatment, as revealed by western blot. In all tested cell lines, the expression of histone gH2AX, a marker of DNA double-strand breaks, after combined drug-IR treatment was higher and its decay rate was slower than those after each single treatment modality. Drug-IR treatment also resulted in impaired cell-cycle progression, as indicated by S-phase depletion and G2/M arrest. In addition, the cell cycle-associated proteins, Cdk1 and Cdk4, were downregulated after Hsp90 inhibition. INTERPRETATION: These findings show that the novel inhibitors of Hsp90 can radiosensitise tumour cell lines of different entities through destabilisation and depletion of several Hsp90 client proteins, thus causing the depletion of S phase and G2/M arrest, increased DNA damage and repair protraction and, to some extent, apoptosis. The results might have important implications for the radiotherapy of solid tumours.

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

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

et al. 2010

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“…Cell survival was measured by a colony formation assay (20). Briefly, cells were seeded in 24-cm 2 flasks and incubated for ~24 h before treatment with scriptaid or TSA.…”

Section: Methodsmentioning

confidence: 99%

Scriptaid, a novel histone deacetylase inhibitor, enhances the response of human tumor cells to radiation

Kuribayashi

Ohara²,

Sora³

et al. 2009

Int J Mol Med

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Abstract. A group of histone deacetylase (HDAC) inhibitors has been shown to suppress the growth of a variety of human tumor lines in vitro and in vivo and they are among the most promising candidates for anti-cancer therapeutic agents. We investigated the ability of scriptaid, a novel HDAC inhibitor and trichostatin A (TSA) to enhance cell killing by radiation in radioresistant SQ-20B cells derived from human head and neck squamous carcinoma. SQ-20B cells were treated with scriptaid or TSA in combination with radiation. Cell survival was determined by a colony formation assay and protein levels were examined by Western blotting. DNA double strand breaks were measured by a Á-H2AX focus assay. Radiosensitization was observed for SQ-20B cells incubated with scriptaid at 5 μM or TSA at 0.1 μM for 24 h. Radiosensitization by scriptaid was accompanied by a prolonged retention of Á-H2AX foci, suggesting that the enhancement of radiation cell killing by scriptaid involved inhibition of DNA double strand break repair. In addition, treatment with scriptaid suppressed expression of Ku80, but not Ku70. Scriptaid may be a useful radiosensitizer in the treatment of radioresistant human carcinomas.

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“…(46,51) We and others have reported that Hsp90 inhibitor geldanamycin and its less toxic derivative 17AAG sensitizes tumor cells, but not normal cells, to radiation. (52)(53)(54) These findings led us to investigate radiosensitization by 17AAG in multicellular spheroids. Spheroids are tumor cell aggregates growing in a three-dimensional structure that simulate the growth and microenvironmental conditions of in vivo tumors.…”

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Heat shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

et al. 2005

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Activation of the PI3K-Akt pathway is known to induce tumor radioresistance. In the current study, we examined the ability of 17AAG, which decreases the levels of Hsp90 client proteins including components of the PI3K-Akt pathway, to sensitize radioresistant human squamous cell carcinoma cells to Xirradiation. Human squamous cell carcinoma cell lines (SQ20B, SCC61 and SCC13) were incubated for 16 h at 37°°°°C in medium containing 17AAG. Radiation sensitivity was determined by clonogenic assays, and protein levels were examined by western blotting. Apoptosis was determined in monolayer cells by AO/EB double staining and in spheroids using the TdT-mediated dUTP nick end labeling assay. 17AAG (0.2 µ µ µ µM) enhanced the radiosensitivity more effectively in radioresistant SQ20B and SCC13 cells than in radiosensitive SCC61 cells. However, in all three cell lines, 17AAG increased radiation-induced apoptosis by reducing the expression of EGFR and ErbB-2 and inhibiting the phosphorylation of Akt. Furthermore, 17AAG (1 µ µ µ µM) sensitized SQ20B spheroids to radiation, and inhibition of Akt activation by 17AAG increased radiation-induced apoptosis in spheroids. The findings suggest that 17AAG effectively sensitizes radioresistant cells to radiation by inhibiting the PI3K-Akt pathway. Targeting the PI3K-Akt pathway with 17AAG could be a useful strategy for radiosensitization of carcinomas. (Cancer Sci 2005; 96: 911-917) R adiation therapy is commonly used for squamous cell carcinoma of the head and neck because of its minimal cosmetic effects and its ability to preserve voice in laryngeal cancer. However, treatment failure correlates with a poorer prognosis and decreased patient survival.The EGFR family contributes to resistance to radiation and chemotherapy in many human tumors, including head and neck cancer.(1-14) ErbB-2, a member of the EGFR family, is also overexpressed in 30% of breast tumors as well as in a significant number of other cancers. (15,16) Blockade of the EGFRmediated signaling pathway enhances the sensitivity of tumor cells to radiation and several chemotherapeutic agents.The PI3K-Akt pathway is a major downstream pathway initiated by activation of the EGFR family members. (17)(18)(19)(20)(21) This pathway plays an important role in cell growth and survival. (22,23) The serine/threonine kinase Akt (also known as protein kinase B) is thought to be a downstream target of PI3K. Akt activation is responsible for desensitizing cells to apoptotic stimuli. This occurs by regulation of the transcriptional activity of both Forkhead family members (24,25) and NF-κB, (26,27) and through phosphorylation and inactivation of the apoptotic machinery including Bcl-2 homolog, Bad (28,29) and caspase-9.(30) Furthermore, Akt is amplified or overexpressed in a wide variety of human tumors.(31-33) PTEN, a tumor suppressor gene, is thought to negatively regulate the PI3K-Akt pathway.(34-36) Mutations causing PTEN to be functionally inactive are frequently detected in many human cancers and enhance Akt activity.(37) Akt acti...

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Geldanamycin, an inhibitor of Hsp90, sensitizes human tumour cells to radiation

Abstract: Targeting Hsp90 with GA provides a promising experimental strategy for radiosensitization of carcinoma.

Cited by 74 publications

References 19 publications

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

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

Scriptaid, a novel histone deacetylase inhibitor, enhances the response of human tumor cells to radiation

Heat shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis

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