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Pyrotinib Sensitizes 5-Fluorouracil-Resistant HER2+ Breast Cancer Cells to 5-Fluorouracil

Jianing Yi*, Shuai Chen*, Pingyong Yi, Jinlin Luo*, Meng Fang*, Yang Du*, Lianhong Zou*, Peizhi Fan*

* Surgical Department of Breast and Thyroid Gland, The First Affiliated Hospital of Hunan Normal University/ Hunan Provincial People’s Hospital, Changsha, P. R. China
† Department of Oncology, Changsha Kexin Cancer Hospital, Changsha, P. R. China

Oncology Research 2020, 28(5), 519-831. https://doi.org/10.3727/096504020X15960154585410

Abstract

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for breast cancer. However, acquired chemoresistance leads to a loss of its efficacy; methods to reverse are urgently needed. Some studies have shown that pyrotinib, an ErbB receptor tyrosine kinase inhibitor, is effective against HER2+ breast cancer. However, whether pyrotinib sensitizes 5-FU-resistant breast cancer cells to 5-FU is unknown. We hypothesized that the combination of pyrotinib and 5-FU would show synergistic antitumor activity, and pyrotinib could reverse 5-FU resistance in HER2+ breast cancer cells in vitro and in vivo. Our data showed that pyrotinib inhibited the growth of 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. 5-FU remarkably suppressed the growth of SKBR-3 and MAD-MB-453 cells. However, SKBR-3/FU and MADMB-453/FU cells showed resistance to 5-FU. A combination of pyrotinib and 5-FU resulted in the synergistic inhibition of the growth of the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines. Pyrotinib decreased significantly the IC50 values of 5-FU and the thymidylate synthase (TS) mRNA expression levels in the 5-FU-resistant SKBR-3/FU and MDA-MB-453/FU cell lines and the parental cell lines and increased significantly the intracellular concentration of 5-FU in SKBR-3/FU and MDA-MB-453/FU cells. In addition, pyrotinib reduced the ABCG2 mRNA and protein expression levels in SKBR-3/FU and MDA-MB- 453/FU cells and downregulated the protein expression levels of pAKT, pHER2, and pHER4 in all four cell lines. After TS or ABCG2 in 5-FU-resistant breast cancer cells was knocked down, the sensitivity of SKBR-3/ FU and MDA-MB-453/FU cells to 5-FU was restored. Moreover, in vivo experiments demonstrated that pyrotinib in combination with 5-FU more effectively inhibited SKBR-3/FU tumor growth than either pyrotinib or 5-FU alone. In conclusion, our findings suggest that pyrotinib could restore sensitivity of 5-FU-resistant HER2+ breast cancer cells to 5-FU through downregulating the expression levels of TS and ABCG2.

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APA Style
Yi, J., Chen, S., Yi, P., Luo, J., Fang, M. et al. (2020). Pyrotinib sensitizes 5-fluorouracil-resistant her2<sup>+</sup> breast cancer cells to 5-fluorouracil. Oncology Research, 28(5), 519-831. https://doi.org/10.3727/096504020X15960154585410
Vancouver Style
Yi J, Chen S, Yi P, Luo J, Fang M, Du Y, et al. Pyrotinib sensitizes 5-fluorouracil-resistant her2<sup>+</sup> breast cancer cells to 5-fluorouracil. Oncol Res. 2020;28(5):519-831 https://doi.org/10.3727/096504020X15960154585410
IEEE Style
J. Yi et al., "Pyrotinib Sensitizes 5-Fluorouracil-Resistant HER2<sup>+</sup> Breast Cancer Cells to 5-Fluorouracil," Oncol. Res., vol. 28, no. 5, pp. 519-831. 2020. https://doi.org/10.3727/096504020X15960154585410



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