Journal
CANCER SCIENCE
Volume 109, Issue 10, Pages 3294-3304Publisher
WILEY
DOI: 10.1111/cas.13779
Keywords
5-fluorouracil; bevacizumab; chemosensitization; thymidine phosphorylase; VEGFA; VEGFR2 blockade
Categories
Funding
- China Creation of New Drugs Key Technology Projects [2015ZX09501001, 2017ZX09304-021]
- China National Nature Science Foundation [81573496, 81530098, 81573494]
- Foundation for Innovative Research Groups of the National Natural Science Foundation of China [81421005]
- Jiangsu Province Nature Science Foundation [BK20160076]
- Project Program of State Key Laboratory of Natural Medicines [SKLNMZZCX201608]
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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 thecytotoxicity of 5-FU via TP upregulation. We provide data to better understand how Bv synergizes with 5-FU from metabolic perspective, and itmay give clues to the superiority of Bv in combination with fluoropyrimidine drugscompared to other chemotherapeutic drugs in colon cancer.
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