Radiosensitizing effect of the novel Hsp90 inhibitor NVP-AUY922 in human tumour cell lines silenced for Hsp90α

Stingl, Lavinia; Niewidok, Natalia; Müller, Nicole; Selle, Martina; Djuzenova, Cholpon S.; Flentje, Michael

doi:10.1007/s00066-012-0080-9

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…These findings support the results of our γ-H2AX foci assay in which we observed increased production and persistence of radiation-induced DNA DSBs in cells treated with AUY922. Our observations that AUY922 causes a G2-M cell cycle arrest and downregulates components of the PI3K-AKT-mTOR pathway were consistent with other studies in non-prostate cancer cell lines [136,137]. With such compelling pre-clinical data we believe that HSP90 inhibition serves as a promising adjunct to RT and that combination treatment is warranted.…”

Section: Candidate Targeted Agents As Radiosensitizers In Prostatesupporting

confidence: 90%

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

Alcorn

Walker

Gandhi

et al. 2013

IJMS

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As our understanding of the molecular pathways driving tumorigenesis improves and more druggable targets are identified, we have witnessed a concomitant increase in the development and production of novel molecularly targeted agents. Radiotherapy is commonly used in the treatment of various malignancies with a prominent role in the care of prostate cancer patients, and efforts to improve the therapeutic ratio of radiation by technologic and pharmacologic means have led to important advances in cancer care. One promising approach is to combine molecularly targeted systemic agents with radiotherapy to improve tumor response rates and likelihood of durable control. This review first explores the limitations of preclinical studies as well as barriers to successful implementation of clinical trials with radiosensitizers. Special considerations related to and recommendations for the design of preclinical studies and clinical trials involving molecularly targeted agents combined with radiotherapy are provided. We then apply these concepts by reviewing a representative set of targeted therapies that show promise as radiosensitizers in the treatment of prostate cancer.

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Section: Candidate Targeted Agents As Radiosensitizers In Prostatesupporting

confidence: 90%

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

Alcorn

Walker

Gandhi

et al. 2013

IJMS

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“…26,39 Targeting Hsp90 with classic geldanamycin inhibitors and more recently with nongeldanamycin based inhibitors, such as AUY922, has demonstrated radiosensitization of cancer cell lines derived from several different histologies. [19][20][21][22][23][24][31][32][33][34][35] Hsp90 inhibition offers the theoretical possibility of potent radiosensitization through broad downregulation of multiple critical radioresistance pathways whose components are members of the Hsp90 clientele, such as signal transduction pathways (PI3K-Akt-mTOR) [12][13][14] and DNA damage response (DDR) pathways (ATR/Chk1). 31,38,40 This study suggests that AUY922 may indeed impart radiosensitization through multiple mechanisms: (1) reassortment of prostate cancer cells into G 2 -M, (2) downregulation of the PI3K-Akt-mTOR radioresistance pathway and (3) downregulation of the ATR-Chk1 DDR pathway.…”

Section: Auy922 Induced a G 2 -M Arrest In Prostate Cancer Cell Linesmentioning

confidence: 99%

“…Our observations that AUY922 causes a G 2 -M cell cycle arrest and downregulates components of the PI3K-AktmTOR pathway are consistent with other studies in non-prostate cancer cell lines. 32,33 A key factor for the clinical success of a radiosensitizer is the ability to selectively radiosensitize only tumor cells and not normal tissues. Previous in vitro preclinical studies have demonstrated that geldanamycin Hsp90 inhibitors do not radiosensitize non-cancerous cell lines.…”

Section: Auy922 Induced a G 2 -M Arrest In Prostate Cancer Cell Linesmentioning

confidence: 99%

Novel Hsp90 Inhibitor NVP-AUY922 Radiosensitizes Prostate Cancer Cells

Gandhi

Wild

Aziz

et al. 2012

International Journal of Radiation Oncology*Biology*Physics

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Purpose/Objective(s): Recent studies have suggested a reciprocal negative feedback mechanism between the androgen receptor (AR) and PI3K-AKT-mTOR signaling pathways in prostate cancer. These recent data suggest that prostate cancer cells can use either PI3K-AKT-mTOR or AR survival pathways for tumor maintenance and point towards combined inhibition of these pathways as a means to improve cancer treatment. The effects of targeting both pathways concurrently on prostate cancer radioresponse are unknown. Critical components of both the PI3K-AKT-mTOR and AR pathways are client proteins of the molecular chaperone protein, Hsp90, which is overexpressed in many cancers. We sought to test the novel Hsp90 inhibitor, NVP-AUY922, for anti-cancer and radiosensitization properties in prostate cancer cells. Materials/Methods: The effect of the NVP-AUY922 alone and in combination with radiation on prostate cancer cells was examined in vitro. Prostate cancer cell immunoblotting assay was performed to assay for NVP-AUY922 effects on the PI3K-AKT-mTOR, MAPK and AR pathways, as well as additional client proteins ATR and CHK1. We examined NVP-AUY922 effects on prostate cancer cell death using annexinV FACS, clonogenic survival, and cell cycle arrest by FACS and DNA damage repair using 53BP1 and gamma-H2AX immunofluorescence. Hind-flank Myc-CaP and PC3 xenograft models were used to examine tumor growth delay following NVP-AUY922 treatment with or without radiation. Results: NVP-AUY922 was able to simultaneously downregulate the PI3K-AKT-mTOR and AR pathways in PC3 and Myc-CaP cells at nanomolar levels (10-50 nM). NVP-AUY922 was able to dramatically radiosensitize both PC3 and Myc-CaP cells at similar levels per clonogenic survival assays. NVP-AUY922 radiosensitization was correlated with delayed repair of DNA double-strand breaks (DSBs) in Myc-CaP cells as per DSB foci assays. Finally, preliminary xenograft experiments demonstrated the ability of NVP-AUY922 and radiation to further delay tumor growth in vivo as compared to either treatment alone (p < 0.05). Conclusions: NVP-AUY922 targets both the AR and PI3K-AKT-mTOR pathways resulting in inhibition of DSB repair and radiosensitization in vitro and in vivo. Our results provide a framework for clinical translation of NVP-AUY922 in combination with radiation therapy for prostate cancer.

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“…However, neither pre-silencing of Hsp90 nor that of Hsp70 increases the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 [14]. Alternatively, the induction of Hsp70 after pharmacological Hsp90 inhibition can be suppressed by concomitant PI3K inhibition with the pyridofuropyrimidine PI-103, a dual PI3K and mTOR inhibitor [15].…”

Section: Introductionmentioning

confidence: 99%

Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule

et al. 2016

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Inhibition of Hsp90 can increase the radiosensitivity of tumor cells. However, inhibition of Hsp90 alone induces the anti-apoptotic Hsp70 and thereby decreases radiosensitivity. Therefore, preventing Hsp70 induction can be a promising strategy for radiosensitization. PI-103, an inhibitor of PI3K and mTOR, has previously been shown to suppress the up-regulation of Hsp70. Here, we explore the impact of combining PI-103 with the Hsp90 inhibitor NVP-AUY922 in irradiated glioblastoma and colon carcinoma cells. We analyzed the cellular response to drug-irradiation treatments by colony-forming assay, expression of several marker proteins, cell cycle progression and induction/repair of DNA damage. Although PI-103, given 24 h prior to irradiation, slightly suppressed the NVP-AUY922-mediated up-regulation of Hsp70, it did not cause radiosensitization and even diminished the radiosensitizing effect of NVP-AUY922. This result can be explained by the activation of PI3K and ERK pathways along with G1-arrest at the time of irradiation. In sharp contrast, PI-103 not only exerted a radiosensitizing effect but also strongly enhanced the radiosensitization by NVP-AUY922 when both inhibitors were added 3 h before irradiation and kept in culture for 24 h. Possible reasons for the observed radiosensitization under this drug-irradiation schedule may be a down-regulation of PI3K and ERK pathways during or directly after irradiation, increased residual DNA damage and strong G2/M arrest 24 h thereafter. We conclude that duration of drug treatment before irradiation plays a key role in the concomitant targeting of PI3K/mTOR and Hsp90 in tumor cells.

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Radiosensitizing effect of the novel Hsp90 inhibitor NVP-AUY922 in human tumour cell lines silenced for Hsp90α

Cited by 6 publications

References 22 publications

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

Molecularly Targeted Agents as Radiosensitizers in Cancer Therapy—Focus on Prostate Cancer

Novel Hsp90 Inhibitor NVP-AUY922 Radiosensitizes Prostate Cancer Cells

Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule

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