Abstract
Emerging evidence has demonstrated that stromal cell-derived factor 1 (SDF-1) and its cognate receptor CXCR4 have critical roles in tumorigenesis, angiogenesis and metastasis. In this study, we demonstrated the significant inhibitory effects of a novel chemically synthetic peptide (E5) on the CXCR4/CXCL12 axis in breast cancer both in vitro and in vivo. E5 was capable of specifically binding to the murine breast cancer cell line 4T1, remarkably inhibiting CXCL12- or stromal cell (MS-5)-induced migration, and adhesion and sensitizing 4T1 cells to multiple chemotherapeutic drugs. Furthermore, E5 combined with either paclitaxel or cyclophosphamide significantly inhibited tumor growth in a breast cancer model. Mechanistic studies implied that E5 can inhibit the expression of CXCR4 to block the CXCL12-mediated recruitment of endothelial progenitor cells and repress CXCR4 downstream of the Akt and Erk signaling pathway, which are involved in tumor angiogenesis and progression. Further pharmacokinetic evaluation suggested that E5 has an acceptable stability, with a half-life of 10 h in healthy mice. In conclusion, E5 demonstrates a promising anti-tumor effect and could be a potential chemotherapeutic sensitizer to improve current clinical breast cancer therapies.
Highlights
According to the latest cancer statistics, breast cancer has the highest incidence rates in women and is predicted to account for 30% of all new cancers among women in 2017.1 death caused by breast cancer has decreased in recent years, it was the leading cause of cancer death in women between 20 and 49 years of age prior to 2013, and remained that way in 2014 for women between 20 and 39 years of age.[1]
When activated by its cognate ligand CXCL12, called stromal-derived factor 1α (SDF-1α), which is secreted by stromal cells including fibroblasts and endothelial cells, CXCR4 mediates tumor cell survival and proliferation, which enhances primary tumor progression, angiogenesis and breast cancer metastasis.[4,5]
E5 has specific affinity to 4T1 breast cancer cells and human umbilical vein endothelial cells (HUVECs) First, we examined the expression of CXCR4 in a murine breast cancer cell line (4T1), HUVECs and a murine stromal cell line (MS-5)
Summary
According to the latest cancer statistics, breast cancer has the highest incidence rates in women and is predicted to account for 30% of all new cancers among women in 2017.1 death caused by breast cancer has decreased in recent years, it was the leading cause of cancer death in women between 20 and 49 years of age prior to 2013, and remained that way in 2014 for women between 20 and 39 years of age.[1]. Encouraged by the significant inhibitory effects of E5 on the CXCR4/CXCL12 axis, in this work, we applied E5 to breast cancer cells and mouse models to investigate whether E5 could sensitize
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