Bingxin Gu1,2,3,4,5, Shuai Liu1,2,3,4,5, Yuyun Sun1,2,3,4,5, Jianping Zhang1,2,3,4,5, Yongping Zhang1,2,3,4,5, Xiaoping Xu1,2,3,4,5, Huiyu Yuan1,2,3,4,5, Mingwei Wang1,2,3,4,5, Yingjian Zhang1,2,3,4,5, Zhongyi Yang6,7,8,9,10. 1. Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Xuhui District, Shanghai, China. 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. 3. Center for Biomedical Imaging, Fudan University, Shanghai, China. 4. Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China. 5. Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai, China. 6. Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, No. 270, Dong'an Road, Xuhui District, Shanghai, China. yangzhongyi21@163.com. 7. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. yangzhongyi21@163.com. 8. Center for Biomedical Imaging, Fudan University, Shanghai, China. yangzhongyi21@163.com. 9. Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China. yangzhongyi21@163.com. 10. Key Laboratory of Nuclear Physics and Ion-beam Application (MOE), Fudan University, Shanghai, China. yangzhongyi21@163.com.
Abstract
PURPOSE: Apoptosis may be an indication of success therapy, and precise detection of apoptosis can provide instructional suggestions in the therapy management of malignant tumors. PROCEDURES: We used CNE-1 cell lines for in vitro experiments, and colony formation assay, CCK-8 assay, cell apoptosis analysis, and western blotting were performed. For in vivo experiments, subcutaneous xenotransplanted tumor models of CNE-1 in nude mice were established. Then, small animal positron emission tomography/X-ray computed tomography (PET/CT) images were acquired by tail intravenous injection of 2-(5-[18F]fluoropentyl)-2-methyl-malonic acid ([18F]ML-10) or 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) before and 24 h and 48 h after treatment. Moreover, expression of epidermal growth factor receptor (EGFR), Ki-67, Glut-1, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was examined by immunohistochemical examination. Tumor volumes of mice were recorded every 2 days. RESULTS: In the presence of Cetuximab, the number of colonies of CNE-1 cells decreased significantly after irradiation at 1 and 2 Gy. In addition, Cetuximab increased the radiation-induced cytotoxicity and apoptosis of CNE-1 cells. Mechanistic studies demonstrated that Cetuximab enhanced radiosensitivity by suppressing the EGFR/PI3-K/AKT pathway. In PET/CT imaging, the tumors showed clear uptake of [18F]ML-10 at 24 h and 48 h after combined treatment, and the value of tumor/muscle (T/M) and SUVmax (the max of standard uptake value) was significantly higher than those of the other three groups. The T/M of [18F]ML-10 uptake showed a positive correlation of 0.926 with the apoptosis index (P < 0.001). However, the uptake of [18F]FDG in tumors exhibited no trend among the four groups. The T/M of [18F]FDG revealed a positive correlation of 0.926 with Glut-1 intensity (P < 0.001). CONCLUSIONS: Our work revealed that Cetuximab could increase the radiosensitivity of CNE-1 cells both in vitro and in vivo. Apoptosis imaging with [18F]ML-10 PET/CT is a promising modality for application in the response prediction of nasopharyngeal carcinoma.
PURPOSE: Apoptosis may be an indication of success therapy, and precise detection of apoptosis can provide instructional suggestions in the therapy management of malignant tumors. PROCEDURES: We used CNE-1 cell lines for in vitro experiments, and colony formation assay, CCK-8 assay, cell apoptosis analysis, and western blotting were performed. For in vivo experiments, subcutaneous xenotransplanted tumor models of CNE-1 in nude mice were established. Then, small animal positron emission tomography/X-ray computed tomography (PET/CT) images were acquired by tail intravenous injection of 2-(5-[18F]fluoropentyl)-2-methyl-malonic acid ([18F]ML-10) or 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) before and 24 h and 48 h after treatment. Moreover, expression of epidermal growth factor receptor (EGFR), Ki-67, Glut-1, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was examined by immunohistochemical examination. Tumor volumes of mice were recorded every 2 days. RESULTS: In the presence of Cetuximab, the number of colonies of CNE-1 cells decreased significantly after irradiation at 1 and 2 Gy. In addition, Cetuximab increased the radiation-induced cytotoxicity and apoptosis of CNE-1 cells. Mechanistic studies demonstrated that Cetuximab enhanced radiosensitivity by suppressing the EGFR/PI3-K/AKT pathway. In PET/CT imaging, the tumors showed clear uptake of [18F]ML-10 at 24 h and 48 h after combined treatment, and the value of tumor/muscle (T/M) and SUVmax (the max of standard uptake value) was significantly higher than those of the other three groups. The T/M of [18F]ML-10 uptake showed a positive correlation of 0.926 with the apoptosis index (P < 0.001). However, the uptake of [18F]FDG in tumors exhibited no trend among the four groups. The T/M of [18F]FDG revealed a positive correlation of 0.926 with Glut-1 intensity (P < 0.001). CONCLUSIONS: Our work revealed that Cetuximab could increase the radiosensitivity of CNE-1 cells both in vitro and in vivo. Apoptosis imaging with [18F]ML-10 PET/CT is a promising modality for application in the response prediction of nasopharyngeal carcinoma.
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