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...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.展开更多
基金This work was supported by the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-3-004)the Key Project of the Major Research Plan from the National Natural Science Foundation of China(91127043).
文摘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.
