Cargando…
Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway
Bevacizumab (Bv) can be used synergistically with fluoropyrimidine‐based chemotherapy to treat colorectal cancer. Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5‐fluorouracil (5‐FU) to tumors and t...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172063/ https://www.ncbi.nlm.nih.gov/pubmed/30151975 http://dx.doi.org/10.1111/cas.13779 |
_version_ | 1783360873500246016 |
---|---|
author | Liu, Wenyue Zhang, Jingwei Yao, Xuequan Jiang, Chao Ni, Ping Cheng, Lingge Liu, Jiali Ni, Suiying Chen, Qianying Li, Qingran Zhou, Kai Wang, Guangji Zhou, Fang |
author_facet | Liu, Wenyue Zhang, Jingwei Yao, Xuequan Jiang, Chao Ni, Ping Cheng, Lingge Liu, Jiali Ni, Suiying Chen, Qianying Li, Qingran Zhou, Kai Wang, Guangji Zhou, Fang |
author_sort | Liu, Wenyue |
collection | PubMed |
description | Bevacizumab (Bv) can be used synergistically with fluoropyrimidine‐based chemotherapy to treat colorectal cancer. Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5‐fluorouracil (5‐FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti‐tumor effects of 5‐FU in LoVo colon cancer xenograft mice and increased the 5‐FU concentration in tumors without affecting hepatic 5‐FU metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase (TP) in tumors, which mediated the metabolic activation of 5‐FU. Although TP is reported to promote angiogenesis and resistance, the combination of Bv and 5‐FU resulted in anti‐angiogenesis and vessel normalization in tumors, indicating that the elevated TP mainly contributed to the enhanced response to 5‐FU. Bv also induced TP upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 (VEGFR2) antagonist apatinib and VEGFR2 silencing further confirmed TP upregulation. Bv and apatinib both enhanced the cytotoxicity of 5‐FU in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on VEGFR2 blockade and specificity protein 1 activation via MDM2 inhibition. In summary, Bv enhanced the accumulation of 5‐FU in tumors and the cytotoxicity of 5‐FU via TP upregulation. We provide data to better understand how Bv synergizes with 5‐FU from metabolic perspective, and it may give clues to the superiority of Bv in combination with fluoropyrimidine drugs compared to other chemotherapeutic drugs in colon cancer. |
format | Online Article Text |
id | pubmed-6172063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61720632018-10-10 Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway Liu, Wenyue Zhang, Jingwei Yao, Xuequan Jiang, Chao Ni, Ping Cheng, Lingge Liu, Jiali Ni, Suiying Chen, Qianying Li, Qingran Zhou, Kai Wang, Guangji Zhou, Fang Cancer Sci Original Articles Bevacizumab (Bv) can be used synergistically with fluoropyrimidine‐based chemotherapy to treat colorectal cancer. Whether and how it affects the delivery of fluoropyrimidine drugs is unknown. The present study aimed to explore the effect of Bv on the delivery of 5‐fluorouracil (5‐FU) to tumors and the underlying mechanism from metabolic perspective. Bv enhanced the anti‐tumor effects of 5‐FU in LoVo colon cancer xenograft mice and increased the 5‐FU concentration in tumors without affecting hepatic 5‐FU metabolism. Interestingly, Bv remarkably upregulated thymidine phosphorylase (TP) in tumors, which mediated the metabolic activation of 5‐FU. Although TP is reported to promote angiogenesis and resistance, the combination of Bv and 5‐FU resulted in anti‐angiogenesis and vessel normalization in tumors, indicating that the elevated TP mainly contributed to the enhanced response to 5‐FU. Bv also induced TP upregulation in LoVo cancer cells. Treatment with vascular endothelial growth factor receptor 2 (VEGFR2) antagonist apatinib and VEGFR2 silencing further confirmed TP upregulation. Bv and apatinib both enhanced the cytotoxicity of 5‐FU in LoVo cells, but there was no synergism with adriamycin and paclitaxel. We further demonstrated that the effect of Bv was dependent on VEGFR2 blockade and specificity protein 1 activation via MDM2 inhibition. In summary, Bv enhanced the accumulation of 5‐FU in tumors and the cytotoxicity of 5‐FU via TP upregulation. We provide data to better understand how Bv synergizes with 5‐FU from metabolic perspective, and it may give clues to the superiority of Bv in combination with fluoropyrimidine drugs compared to other chemotherapeutic drugs in colon cancer. John Wiley and Sons Inc. 2018-09-25 2018-10 /pmc/articles/PMC6172063/ /pubmed/30151975 http://dx.doi.org/10.1111/cas.13779 Text en © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Liu, Wenyue Zhang, Jingwei Yao, Xuequan Jiang, Chao Ni, Ping Cheng, Lingge Liu, Jiali Ni, Suiying Chen, Qianying Li, Qingran Zhou, Kai Wang, Guangji Zhou, Fang Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
title | Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
title_full | Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
title_fullStr | Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
title_full_unstemmed | Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
title_short | Bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
title_sort | bevacizumab‐enhanced antitumor effect of 5‐fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor a/vascular endothelial growth factor receptor 2‐specificity protein 1 pathway |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172063/ https://www.ncbi.nlm.nih.gov/pubmed/30151975 http://dx.doi.org/10.1111/cas.13779 |
work_keys_str_mv | AT liuwenyue bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT zhangjingwei bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT yaoxuequan bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT jiangchao bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT niping bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT chenglingge bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT liujiali bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT nisuiying bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT chenqianying bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT liqingran bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT zhoukai bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT wangguangji bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway AT zhoufang bevacizumabenhancedantitumoreffectof5fluorouracilviaupregulationofthymidinephosphorylasethroughvascularendothelialgrowthfactoravascularendothelialgrowthfactorreceptor2specificityprotein1pathway |