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Novel PI3K and mTOR Inhibitor NVP-BEZ235 Radiosensitizes Breast Cancer Cell Lines under Normoxic and Hypoxic Conditions

Please always quote using this URN: urn:nbn:de:bvb:20-opus-112708
  • In the present study, we assessed, if the novel dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 radiosensitizes triple negative (TN) MDA-MB-231 and estrogen receptor (ER) positive MCF-7 cells to ionizing radiation under various oxygen conditions, simulating different microenvironments as occurring in the majority of breast cancers (BCs). Irradiation (IR) of BC cells cultivated in hypoxic conditions revealed increased radioresistance compared to normoxic controls. Treatment with NVP-BEZ235In the present study, we assessed, if the novel dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 radiosensitizes triple negative (TN) MDA-MB-231 and estrogen receptor (ER) positive MCF-7 cells to ionizing radiation under various oxygen conditions, simulating different microenvironments as occurring in the majority of breast cancers (BCs). Irradiation (IR) of BC cells cultivated in hypoxic conditions revealed increased radioresistance compared to normoxic controls. Treatment with NVP-BEZ235 completely circumvented this hypoxia-induced effects and radiosensitized normoxic, reoxygenated, and hypoxic cells to similar extents. Furthermore, NVP-BEZ235 treatment suppressed HIF-1α expression and PI3K/mTOR signaling, induced autophagy, and caused protracted DNA damage repair in both cell lines in all tested oxygen conditions. Moreover, after incubation with NVP-BEZ235, MCF-7 cells revealed depletion of phospho-AKT and considerable signs of apoptosis, which were signifi-cantly enhanced by radiation. Our findings clearly demonstrate that NVP-BEZ235 has a clinical relevant potential as a radiosensitizer in BC treatment.show moreshow less

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Metadaten
Author: Sebastian Kuger, Emre Cörek, Bülent Polat, Ulrike Kämmerer, Michael Flentje, Cholpon S. Djuzenova
URN:urn:nbn:de:bvb:20-opus-112708
Document Type:Journal article
Faculties:Medizinische Fakultät / Frauenklinik und Poliklinik
Medizinische Fakultät / Klinik und Poliklinik für Strahlentherapie
Language:English
Year of Completion:2014
Source:Breast Cancer: Basic and Clinical Research 2014:8 39–49 doi: 10.4137/BCBCR.S13693
DOI:https://doi.org/10.4137/BCBCR.S13693
Sonstige beteiligte Institutionen:Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Akt; DNA repair protraction; NVP-BEZ235; Novel PI3K; apoptosis; autophagy; hypoxia; mTOR Inhibitor; radiosensibility
Release Date:2015/05/11
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2014
Licence (German):License LogoCC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell