Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/mTOR inhibitor
| العنوان: | Combined treatment of pancreatic cancer xenograft with 90Y-ITGA6B4-mediated radioimmunotherapy and PI3K/mTOR inhibitor |
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| المؤلفون: | Tsuneo Saga, Winn Aung, Atsushi B. Tsuji, Tatsuya Higashi, Takako Furukawa, Yoshikazu Kurosawa, Aya Sugyo, Yoshinori Ukai, Hitomi Sudo, Katsushi Kouda |
| المصدر: | World Journal of Gastroenterology |
| بيانات النشر: | Baishideng Publishing Group Inc, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Oncology, medicine.medical_specialty, Yttrium-90, medicine.medical_treatment, Mice, Nude, Antineoplastic Agents, Integrin alpha6, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Combined treatment, Internal medicine, Pancreatic cancer, Cell Line, Tumor, medicine, Animals, Humans, Yttrium Radioisotopes, PI3K/AKT/mTOR pathway, business.industry, Anti-integrin α6β4 antibody, Integrin beta4, Gastroenterology, Imidazoles, Antibodies, Monoclonal, General Medicine, Basic Study, Radioimmunotherapy, medicine.disease, Discovery and development of mTOR inhibitors, Xenograft Model Antitumor Assays, NVP-BEZ235, Pancreatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Quinolines, Female, business, Proto-Oncogene Proteins c-akt, Signal Transduction |
| الوصف: | AIM To investigate the therapeutic effect of combined integrin α6β4-targeted radioimmunotherapy (RIT) and PI3K/mTOR inhibitor BEZ235 in a pancreatic cancer model. METHODS Phosphorylation of Akt, mTOR, the downstream effectors eukaryotic initiation factor 4E binding protein 1 (4EBP1) and S6 ribosomal protein (S6) were evaluated in BxPC-3 human pancreatic cancer cells treated with Yttrium-90 (90Y) labeled anti-integrin α6β4 antibody (ITGA6B4) and BEZ235 by western blotting. The cytotoxic effect of BEZ235 was investigated using a colony formation assay. Therapeutic efficacy enhancement by oral BEZ235 administration was assessed using mice bearing BxPC-3 xenograft tumors. Tumor volume measurements and immunohistochemical analyses (cell proliferation marker Ki-67, DNA damage marker p-H2AX and p-4EBP1 staining) of tumors were performed for evaluation of combined treatment with 90Y-ITGA6B4 plus BEZ235, or each arm alone. RESULTS We found that phosphorylation of Akt (p-Akt), 4EBP1 (p-4EBP1) and S6 (p-S6) was inhibited by BEZ235. Colony formation in BxPC-3 cells was additively suppressed by the combination of 90Y-ITGA6B4 and BEZ235. Pretreatment with BEZ235 before 90Y-ITGA6B4 exposure resulted in significant reduction of cells plating efficiency (PE) (0.54 ± 0.11 vs 2.81 ± 0.14 with 185 kBq/mL 90Y-ITGA6B4 exposure, P < 0.01; 0.39 ± 0.08 vs 1.88 ± 0.09 with 370 kBq/mL 90Y-ITGA6B4 exposure, P < 0.01) when 5 × 103 cells per dish were plated. In vivo , the combined treatment with 90Y-ITGA6B4 plus BEZ235 enhanced the inhibition of tumor growth and statistically significant differences of relative tumor volume were observed for 27 d after the treatment start date when compared with the 90Y-ITGA6B4 single injection treatment (1.03 ± 0.38 vs 1.5 ± 0.15 at Day 27, P < 0.05), and for 41 d when compared with the BEZ235 treatment alone (1.8 ± 0.7 vs 3.14 ± 1.19 at Day 41, P < 0.05). Tumors from treatment groups showed reduction in volumes, decreased Ki-67-positive cells, increased p-H2AX-positive cells and decreased p-4EBP1 expression. CONCLUSION The therapeutic efficacy of 90Y-ITGA6B4-RIT can be improved by combining with dual PI3K and mTOR inhibitor, BEZ235, in a pancreatic cancer model suggesting potential clinical application. Key words: Radioimmunotherapy; Pancreatic cancer; anti-integrin α6β4 antibody; Yttrium-90; NVP-BEZ235 |
| اللغة: | English |
| تدمد: | 2219-2840 1007-9327 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f57e70b20205353d38f0cdc6ccaf2846Test http://europepmc.org/articles/PMC5698248Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f57e70b20205353d38f0cdc6ccaf2846 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22192840 10079327 |
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