Trifluridine selectively inhibits cell growth and induces cell apoptosis of triple-negative breast cancer

Juan Li; Jie Liu; Riqi Wang; He Chen; Cui Li; Minggang Zhao; Fang He; Yaochun Wang; Peijun Liu

Trifluridine selectively inhibits cell growth and induces cell apoptosis of triple-negative breast cancer

Am J Cancer Res. 2020 Feb 1;10(2):507-522. eCollection 2020.

Authors

Juan Li^{1

2}, Jie Liu^{1

2}, Riqi Wang^{1

2}, He Chen^{1

2}, Cui Li^{1

2}, Minggang Zhao^{1

2}, Fang He^{1

2}, Yaochun Wang^{1

2}, Peijun Liu^{1

2}

Affiliations

¹ Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an, Shaanxi, PR China.
² Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an, Shaanxi, PR China.

PMID: 32195023
PMCID: PMC7061745

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive cancers with a high rate of recurrence and metastasis. Trifluridine (TFT) is a thymidine analog to target thymidylate synthase (TS) and has potent ant-herpes simplex virus activity. However, little is known whether and how TFT treatment can modulate the growth of TNBC. In this study, we found that treatment with TFT selectively inhibited the proliferation of TNBC cells and triggered their apoptosis. TFT treatment significantly up-regulatd the expression of G1 phase inhibitor p21 and p27, and pro-apoptotic factor γ-H2AX, Bax and cleaved caspase-7 in TNBC cells. TFT treatment significantly down-regulated the expression of proliferating cell nuclear antigen (PCNA), minichromosome maintenance component 7 (MCM7) and anti-apoptotic Bcl-2 in TNBC cells. TFT treatment significantly mitigated the growth of implanted mouse TNBC in vivo, associated with increased expression of γ-H2AX and cleaved caspase-7 in mouse TNBC tumors. TS expression was up-regulated in breast cancer, particularly in TNBC tissues, and up-regulated TS expression was significantly associated with a shorter overall survival and disease free survival in TNBC patients. TS silencing selectively decreased the proliferation of TNBC cells, but did not trigger their apoptosis. Treatment with TFT induced DNA double strand break (DSB) and damages in TNBC cells. Collectively, TFT selectively inhibited the growth of TNBC by inducing chromosome instability and inhibiting thymidine synthase. Therefore, TFT may be valuable for the intervention of TNBC.

Keywords: Trifluridine; cell apoptosis; chromosome instability; proliferation; triple-negative breast cancer.