Open Access
ARTICLE
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.
Keywords
Cite This Article
Yi, J., Chen, S., Yi, P., Luo, J., Fang, M. et al. (2020). Pyrotinib Sensitizes 5-Fluorouracil-Resistant HER2
+ Breast Cancer Cells to 5-Fluorouracil.
Oncology Research, 28(5), 519–831.