Open AccessBevacizumab‐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
Author(s) -
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
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13779
Subject(s) - downregulation and upregulation , thymidine phosphorylase , bevacizumab , angiogenesis , cancer research , vascular endothelial growth factor , vascular endothelial growth factor a , paclitaxel , pharmacology , medicine , chemistry , cancer , chemotherapy , biochemistry , vegf receptors , gene
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 ( VEGFR 2) antagonist apatinib and VEGFR 2 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 VEGFR 2 blockade and specificity protein 1 activation via MDM 2 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.