2017年11月
Combined treatment of pancreatic cancer xenograft with Y-90-ITGA6B4-mediated radioimmunotherapy and PI3K/mTOR inhibitor
WORLD JOURNAL OF GASTROENTEROLOGY
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- 巻
- 23
- 号
- 42
- 開始ページ
- 7551
- 終了ページ
- 7562
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.3748/wjg.v23.i42.7551
- 出版者・発行元
- BAISHIDENG PUBLISHING GROUP INC
AIM
To investigate the therapeutic effect of combined integrin alpha 6 beta 4-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 (Y-90) labeled anti-integrin alpha 6 beta 4 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 Y-90-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 Y-90-ITGA6B4 and BEZ235. Pretreatment with BEZ235 before Y-90-ITGA6B4 exposure resulted in significant reduction of cells plating efficiency (PE) (0.54 +/- 0.11 vs 2.81 +/- 0.14 with 185 kBq/mL Y-90-ITGA6B4 exposure, P < 0.01; 0.39 +/- 0.08 vs 1.88 +/- 0.09 with 370 kBq/mL Y-90-ITGA6B4 exposure, P < 0.01) when 5 x 10(3) cells per dish were plated. In vivo, the combined treatment with Y-90-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 Y-90-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 Y-90-ITGA6B4-RIT can be improved by combining with dual PI3K and mTOR inhibitor, BEZ235, in a pancreatic cancer model suggesting potential clinical application.
To investigate the therapeutic effect of combined integrin alpha 6 beta 4-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 (Y-90) labeled anti-integrin alpha 6 beta 4 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 Y-90-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 Y-90-ITGA6B4 and BEZ235. Pretreatment with BEZ235 before Y-90-ITGA6B4 exposure resulted in significant reduction of cells plating efficiency (PE) (0.54 +/- 0.11 vs 2.81 +/- 0.14 with 185 kBq/mL Y-90-ITGA6B4 exposure, P < 0.01; 0.39 +/- 0.08 vs 1.88 +/- 0.09 with 370 kBq/mL Y-90-ITGA6B4 exposure, P < 0.01) when 5 x 10(3) cells per dish were plated. In vivo, the combined treatment with Y-90-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 Y-90-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 Y-90-ITGA6B4-RIT can be improved by combining with dual PI3K and mTOR inhibitor, BEZ235, in a pancreatic cancer model suggesting potential clinical application.
- リンク情報
- ID情報
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- DOI : 10.3748/wjg.v23.i42.7551
- ISSN : 1007-9327
- eISSN : 2219-2840
- Web of Science ID : WOS:000414872500006