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

Autor: Suiying Ni, Kai Zhou, Chao Jiang, Qingran Li, Qianying Chen, Lingge Cheng, Jingwei Zhang, Wenyue Liu, Jiali Liu, Guangji Wang, Ping Ni, Xuequan Yao, Fang Zhou
Rok vydání: 2018
Předmět:
Male
Vascular Endothelial Growth Factor A
0301 basic medicine
Cancer Research
Bevacizumab
Pyridines
Sp1 Transcription Factor
VEGFA/VEGFR2 blockade
Angiogenesis
Mice
Nude
bevacizumab
thymidine phosphorylase
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Downregulation and upregulation
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Apatinib
Thymidine phosphorylase
Mice
Inbred BALB C
Neovascularization
Pathologic
Chemistry
Drug Synergism
Proto-Oncogene Proteins c-mdm2
Kinase insert domain receptor
Original Articles
General Medicine
Vascular Endothelial Growth Factor Receptor-2
Xenograft Model Antitumor Assays
chemosensitization
Up-Regulation
5‐fluorouracil
Vascular endothelial growth factor A
Drug Discovery and Delivery
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Colonic Neoplasms
Cancer cell
Cancer research
Original Article
Fluorouracil
Signal Transduction
medicine.drug
Zdroj: Cancer Science
ISSN: 1347-9032
DOI: 10.1111/cas.13779
Popis: 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.
Databáze: OpenAIRE
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