The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Johan Gabrielsson - One of the best experts on this subject based on the ideXlab platform.
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the tumor static exposure tse concept utility application to combination treatment of radiation and Radiosensitizing Agent in tumor xenograft experiments
Annals of Oncology, 2019Co-Authors: El S Bawab, Tim Cardilin, Mats Jirstrand, Astrid Zimmermann, Floriane Lignet, Johan GabrielssonAbstract:Abstract Background We present a pharmacodynamic model that describes the tumor volume evolution during and after treatment with radiation and in combination with a Radiosensitizing Agent. A key contribution is the inclusion of a long-term radiation effect, which allows the model to describe distinct tumor behaviors including tumor eradication and tumor regrowth with different growth rates. Additionally, we introduce the concept of TSE (Tumor Static Exposure), the exposures of one or multiple compounds that result in tumor stasis and provide an example of its utility for optimizing drug combinations in oncology. Methods The model was challenged with data from four treatment groups (Vehicle, radiation, radiation + radiosensitizer 25 or 100 mg/kg) in xenograft study using a clinically-relevant administration schedule (6 weeks treatment, 5 days on/2 days off) and a mixed-effects approach was used for model-fitting. The model incorporated a permanent inhibition of the natural growth rate. This step was required to capture the complete tumor eradication and the observed tumor regrowth with different rates with animals having slower regrowth compared to control animals. The presence of a radiosensitizer will lead to the same tumor evolution as if a higher dose of radiation had been administered. The model was applied to predict exposure combinations that result in tumor eradication using the TSE. Results The developed model captured experimental data from all treatment groups adequately, with the parameter estimates taking biologically reasonable values. Model simulation showed that tumor eradication is observed at total radiation dose of 110 Gy, which is reduced to 80 or 30 Gy with co-administration of 25 or 100 mg/kg of a radiosensitizer. Conclusions The new model can describe different tumor dynamics including tumor eradication and tumor regrowth with different rates. The proposed model can be expanded for radiation in combination with chemical interventions or immunotherapy. The model and TSE can be applied to generate treatment predictions for different dosing schedules or determining drug synergies. The translational utility of the TSE concept is currently under investigation. Legal entity responsible for the study Merck Healthcare KGaA. Funding Tim Cardilin was supported by an education Grant from Merck Healthcare KGaA, Darmstadt, Germany. This work was also partially funded by the Swedish Foundation for Strategic Research (Grant no. AM13-0046). Disclosure S. El Bawab: Full / Part-time employment: Merck Healthcare KGaA. A. Zimmermann: Full / Part-time employment: Merck Healthcare KGaA. F. Lignet: Full / Part-time employment: Merck Healthcare KGaA. All authors have declared no conflicts of interest.
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The tumor static exposure (TSE) concept & utility: Application to combination treatment of radiation and Radiosensitizing Agent in tumor xenograft experiments
Annals of Oncology, 2019Co-Authors: S. El Bawab, Tim Cardilin, Mats Jirstrand, Astrid Zimmermann, Floriane Lignet, Johan GabrielssonAbstract:Abstract Background We present a pharmacodynamic model that describes the tumor volume evolution during and after treatment with radiation and in combination with a Radiosensitizing Agent. A key contribution is the inclusion of a long-term radiation effect, which allows the model to describe distinct tumor behaviors including tumor eradication and tumor regrowth with different growth rates. Additionally, we introduce the concept of TSE (Tumor Static Exposure), the exposures of one or multiple compounds that result in tumor stasis and provide an example of its utility for optimizing drug combinations in oncology. Methods The model was challenged with data from four treatment groups (Vehicle, radiation, radiation + radiosensitizer 25 or 100 mg/kg) in xenograft study using a clinically-relevant administration schedule (6 weeks treatment, 5 days on/2 days off) and a mixed-effects approach was used for model-fitting. The model incorporated a permanent inhibition of the natural growth rate. This step was required to capture the complete tumor eradication and the observed tumor regrowth with different rates with animals having slower regrowth compared to control animals. The presence of a radiosensitizer will lead to the same tumor evolution as if a higher dose of radiation had been administered. The model was applied to predict exposure combinations that result in tumor eradication using the TSE. Results The developed model captured experimental data from all treatment groups adequately, with the parameter estimates taking biologically reasonable values. Model simulation showed that tumor eradication is observed at total radiation dose of 110 Gy, which is reduced to 80 or 30 Gy with co-administration of 25 or 100 mg/kg of a radiosensitizer. Conclusions The new model can describe different tumor dynamics including tumor eradication and tumor regrowth with different rates. The proposed model can be expanded for radiation in combination with chemical interventions or immunotherapy. The model and TSE can be applied to generate treatment predictions for different dosing schedules or determining drug synergies. The translational utility of the TSE concept is currently under investigation. Legal entity responsible for the study Merck Healthcare KGaA. Funding Tim Cardilin was supported by an education Grant from Merck Healthcare KGaA, Darmstadt, Germany. This work was also partially funded by the Swedish Foundation for Strategic Research (Grant no. AM13-0046). Disclosure S. El Bawab: Full / Part-time employment: Merck Healthcare KGaA. A. Zimmermann: Full / Part-time employment: Merck Healthcare KGaA. F. Lignet: Full / Part-time employment: Merck Healthcare KGaA. All authors have declared no conflicts of interest.
Shih-kai Hung - One of the best experts on this subject based on the ideXlab platform.
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Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway.
International journal of molecular medicine, 2014Co-Authors: Fei Ting Hsu, Ling-chien Hung, Moon-sing Lee, Jeng-jong Hwang, Wen-yen Chiou, Yi Lin, Shih-kai HungAbstract:Modern radiation therapy strives to minimize injury to organs while increasing the anticancer effects. The present study aimed to investigate the Radiosensitizing effects of everolimus and to examine the molecular mechanisms responsible for everolimus‑mediated radiosensitization. Radiation in combination with everolimus (30 nM) sensitized Ras-transformed cells to radiation in vitro. Radiation induced apoptotic markers (sub-G1 cell accumulation, membrane inversion and DNA fragmentation) and treatment with everolimus did not promote radiation-induced apoptosis. However, LC3-II expression increased following combination treatment with everolimus and radiation, and the Radiosensitizing effects of everolimus were reversed following transfection with small interfering RNA (siRNA) targeting Beclin 1. In addition, the protein levels of activated S6 kinase 1 (S6K1) were significantly reduced following treatment with everolimus, and the phosphorylation of factor 4E binding protein 1 (4EBP1) was suppressed following combination treatment. Taken together, our data demonstrate that everolimus sensitizes Ras-transformed cells to radiation in vitro. Everolimus-mediated radiosensitization is associated with the autophagy pathway. Thus, everolimus is a novel Radiosensitizing Agent with potential for use in cancer radiotherapy.
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Andrographolide Sensitizes Ras-Transformed Cells to Radiation in vitro and in vivo
International journal of radiation oncology biology physics, 2010Co-Authors: Shih-kai Hung, Ling-chien Hung, Cheng-deng Kuo, Kuan-yi Lee, Moon-sing Lee, Hon-yi Lin, Yu-jen ChenAbstract:Purpose Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the Radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials An H- ras -transformed rat kidney epithelial (RK3E) cell line was used to measure the Radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-κB) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results Concurrent andrographolide treatment (10 μM, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 ± 2.5 days) compared with radiation alone (22 ± 1.5 days; p e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-κB activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-κB activity. Conclusion Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo . Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-κB activity. These observations indicate that andrographolide is a novel Radiosensitizing Agent with potential application in cancer radiotherapy.
Yi Sun - One of the best experts on this subject based on the ideXlab platform.
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the p21 dependent radiosensitization of human breast cancer cells by mln4924 an investigational inhibitor of nedd8 activating enzyme
PLOS ONE, 2012Co-Authors: Dong Yang, Mingjia Tan, Gongxian Wang, Yi SunAbstract:Radiotherapy is a treatment choice for local control of breast cancer. However, intrinsic radioresistance of cancer cells limits therapeutic efficacy. We have recently validated that SCF (SKP1, Cullins, and F-box protein) E3 ubiquitin ligase is an attractive Radiosensitizing target. Here we tested our hypothesis that MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 Activating Enzyme) that inactivates SCF E3 ligase, could act as a novel Radiosensitizing Agent in breast cancer cells. Indeed, we found that MLN4924 effectively inhibited cullin neddylation, and sensitized breast cancer cells to radiation with a sensitivity enhancement ratio (SER) of 1.75 for SK-BR-3 cells and 1.32 for MCF7 cells, respectively. Mechanistically, MLN4924 significantly enhanced radiation-induced G2/M arrest in SK-BR-3 cells, but not in MCF7 cells at early time point, and enhanced radiation-induced apoptosis in both lines at later time point. However, blockage of apoptosis by Z-VAD failed to abrogate MLN4924 radiosensitization, suggesting that apoptosis was not causally related. We further showed that MLN4924 failed to enhance radiation-induced DNA damage response, but did cause minor delay in DNA damage repair. Among a number of tested SCF E3 substrates known to regulate growth arrest, apoptosis and DNA damage response, p21 was the only one showing an enhanced accumulation in MLN4924-radiation combination group, as compared to the single treatment groups. Importantly, p21 knockdown via siRNA partialy inhibited MLN4924-induced G2/M arrest and radiosensitization, indicating a causal role played by p21. Our study suggested that MLN4924 could be further developed as a novel class of radiosensitizer for the treatment of breast cancer.
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radiosensitization of head and neck squamous cell carcinoma by a smac mimetic compound sm 164 requires activation of caspases
Molecular Cancer Therapeutics, 2011Co-Authors: Jie Yang, Theodore S. Lawrence, Meredith A Morgan, Mary A. Davis, Donna Mceachern, Longchuan Bai, Jonathan T Sebolt, Haiying Sun, Shaomeng Wang, Yi SunAbstract:Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small SMAC mimetic compound that promotes degradation of cIAP-1 (also known as BIRC2) and releases active caspases from XIAP inhibitory binding, as a Radiosensitizing Agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via siRNA knockdown or a pan-caspase inhibitor, z-VAD-fmk largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of BCL-2 that blocks caspase activation and apoptosis induction became sensitive to radiation upon BCL-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NFκB activation and TNFα secretion, followed by activation of caspases-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft, while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients.
Ling-chien Hung - One of the best experts on this subject based on the ideXlab platform.
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Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway.
International journal of molecular medicine, 2014Co-Authors: Fei Ting Hsu, Ling-chien Hung, Moon-sing Lee, Jeng-jong Hwang, Wen-yen Chiou, Yi Lin, Shih-kai HungAbstract:Modern radiation therapy strives to minimize injury to organs while increasing the anticancer effects. The present study aimed to investigate the Radiosensitizing effects of everolimus and to examine the molecular mechanisms responsible for everolimus‑mediated radiosensitization. Radiation in combination with everolimus (30 nM) sensitized Ras-transformed cells to radiation in vitro. Radiation induced apoptotic markers (sub-G1 cell accumulation, membrane inversion and DNA fragmentation) and treatment with everolimus did not promote radiation-induced apoptosis. However, LC3-II expression increased following combination treatment with everolimus and radiation, and the Radiosensitizing effects of everolimus were reversed following transfection with small interfering RNA (siRNA) targeting Beclin 1. In addition, the protein levels of activated S6 kinase 1 (S6K1) were significantly reduced following treatment with everolimus, and the phosphorylation of factor 4E binding protein 1 (4EBP1) was suppressed following combination treatment. Taken together, our data demonstrate that everolimus sensitizes Ras-transformed cells to radiation in vitro. Everolimus-mediated radiosensitization is associated with the autophagy pathway. Thus, everolimus is a novel Radiosensitizing Agent with potential for use in cancer radiotherapy.
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Andrographolide Sensitizes Ras-Transformed Cells to Radiation in vitro and in vivo
International journal of radiation oncology biology physics, 2010Co-Authors: Shih-kai Hung, Ling-chien Hung, Cheng-deng Kuo, Kuan-yi Lee, Moon-sing Lee, Hon-yi Lin, Yu-jen ChenAbstract:Purpose Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the Radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials An H- ras -transformed rat kidney epithelial (RK3E) cell line was used to measure the Radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-κB) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results Concurrent andrographolide treatment (10 μM, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 ± 2.5 days) compared with radiation alone (22 ± 1.5 days; p e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-κB activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-κB activity. Conclusion Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo . Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-κB activity. These observations indicate that andrographolide is a novel Radiosensitizing Agent with potential application in cancer radiotherapy.
Moon-sing Lee - One of the best experts on this subject based on the ideXlab platform.
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Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway.
International journal of molecular medicine, 2014Co-Authors: Fei Ting Hsu, Ling-chien Hung, Moon-sing Lee, Jeng-jong Hwang, Wen-yen Chiou, Yi Lin, Shih-kai HungAbstract:Modern radiation therapy strives to minimize injury to organs while increasing the anticancer effects. The present study aimed to investigate the Radiosensitizing effects of everolimus and to examine the molecular mechanisms responsible for everolimus‑mediated radiosensitization. Radiation in combination with everolimus (30 nM) sensitized Ras-transformed cells to radiation in vitro. Radiation induced apoptotic markers (sub-G1 cell accumulation, membrane inversion and DNA fragmentation) and treatment with everolimus did not promote radiation-induced apoptosis. However, LC3-II expression increased following combination treatment with everolimus and radiation, and the Radiosensitizing effects of everolimus were reversed following transfection with small interfering RNA (siRNA) targeting Beclin 1. In addition, the protein levels of activated S6 kinase 1 (S6K1) were significantly reduced following treatment with everolimus, and the phosphorylation of factor 4E binding protein 1 (4EBP1) was suppressed following combination treatment. Taken together, our data demonstrate that everolimus sensitizes Ras-transformed cells to radiation in vitro. Everolimus-mediated radiosensitization is associated with the autophagy pathway. Thus, everolimus is a novel Radiosensitizing Agent with potential for use in cancer radiotherapy.
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Andrographolide Sensitizes Ras-Transformed Cells to Radiation in vitro and in vivo
International journal of radiation oncology biology physics, 2010Co-Authors: Shih-kai Hung, Ling-chien Hung, Cheng-deng Kuo, Kuan-yi Lee, Moon-sing Lee, Hon-yi Lin, Yu-jen ChenAbstract:Purpose Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the Radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials An H- ras -transformed rat kidney epithelial (RK3E) cell line was used to measure the Radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-κB) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results Concurrent andrographolide treatment (10 μM, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 ± 2.5 days) compared with radiation alone (22 ± 1.5 days; p e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-κB activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-κB activity. Conclusion Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo . Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-κB activity. These observations indicate that andrographolide is a novel Radiosensitizing Agent with potential application in cancer radiotherapy.