Improving chemotherapeutics efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering CXCR4/CXCL12 axis
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- 英文论文题名：Improving chemotherapeutics efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering CXCR4/CXCL12 axis
- 论文作者：Li Xiaojin ; Guo Hua ; Duan Hongyang ; Yang Yanlian ; Meng Jie ; Liu Jian ; Wang Chen ; Xu Haiyan
- 英文论文作者：Li Xiaojin ; Guo Hua ; Duan Hongyang ; Yang Yanlian ; Meng Jie ; Liu Jian ; Wang Chen ; Xu Haiyan ; Department of Biomedical Engineering ; Institute of Basic Medical Sciences ; Chinese Academy of Medical Science & Peking Union Medical College ; National Center for Nanoscience and Technology
- 年：2016
- 作者机构：Department of Biomedical Engineering,Institute of Basic Medical Sciences,Chinese Academy of Medical Science & Peking Union Medical College;National Center for Nanoscience and Technology;
- 英文论文关键词：CXCR4 ; antagonist ; AML ; peptide
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会摘要汇编
- 英文会议录名称：Abstracts of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R733.71
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：2
- 文件大小：1355k
- 原文格式：D
- 会议级别：全国
摘要
Objective: Acute myeloid leukemia(AML) cells highly expressing chemokine receptor CXCR4 can actively response to chemokine CXCL12 that is largely secreted by bone marrow stroma, trafficking and homing to the marrow microenvironment, resulting in minimal residual leukemia and relapse. Methods and Results: We designed a novel peptide(E5) that targets CXCR4 and inhibits CXCL12- and stroma-induced adhesion and migration in multiple AML cell lines, displaying anti-AML activity. Mechanistic studies demonstrate that E5 down-regulates CXCL12-induced phosphorylation of Akt, Erk and p38, affecting the cytoskeleton F-actin organization and ultimately resulting in the inhibition of the AML cells responses. We further presented E5's capacity of enhancing the therapeutic efficiency of various chemotherapeutics on AML in vitro and in vivo. Results show that E5 diminished bone marrow stromal cell-provided protection to leukemia cells, significantly increasing the apoptosis induced by chemotherapeutics in AML cells. In an AML mouse xenograft model, E5 induced 1.84-fold increase of circulating AML cells out of protective stroma niche. Combined with vincristine or cyclophosphamide, E5 inhibited infiltration of AML cells into bone marrow, liver and spleen, as well as prolonged the lifespan of AML mice compared with mice treated with chemotherapy alone. In addition, E5 presented no toxicity in vivo.Conclusion: We demonstrated the effect of E5 in inhibiting AML cells from responding to CXCL12- or MS-5 induced activation and eradicating leukemia cells in vitro and in vivo. Furthermore, E5 can reduce tumor burden, significantly improve the efficiency of chemotherapies for AML and extend survival in AML mice.
Objective: Acute myeloid leukemia(AML) cells highly expressing chemokine receptor CXCR4 can actively response to chemokine CXCL12 that is largely secreted by bone marrow stroma, trafficking and homing to the marrow microenvironment, resulting in minimal residual leukemia and relapse. Methods and Results: We designed a novel peptide(E5) that targets CXCR4 and inhibits CXCL12- and stroma-induced adhesion and migration in multiple AML cell lines, displaying anti-AML activity. Mechanistic studies demonstrate that E5 down-regulates CXCL12-induced phosphorylation of Akt, Erk and p38, affecting the cytoskeleton F-actin organization and ultimately resulting in the inhibition of the AML cells responses. We further presented E5's capacity of enhancing the therapeutic efficiency of various chemotherapeutics on AML in vitro and in vivo. Results show that E5 diminished bone marrow stromal cell-provided protection to leukemia cells, significantly increasing the apoptosis induced by chemotherapeutics in AML cells. In an AML mouse xenograft model, E5 induced 1.84-fold increase of circulating AML cells out of protective stroma niche. Combined with vincristine or cyclophosphamide, E5 inhibited infiltration of AML cells into bone marrow, liver and spleen, as well as prolonged the lifespan of AML mice compared with mice treated with chemotherapy alone. In addition, E5 presented no toxicity in vivo.Conclusion: We demonstrated the effect of E5 in inhibiting AML cells from responding to CXCL12- or MS-5 induced activation and eradicating leukemia cells in vitro and in vivo. Furthermore, E5 can reduce tumor burden, significantly improve the efficiency of chemotherapies for AML and extend survival in AML mice.
Objective: Acute myeloid leukemia(AML) cells highly expressing chemokine receptor CXCR4 can actively response to chemokine CXCL12 that is largely secreted by bone marrow stroma, trafficking and homing to the marrow microenvironment, resulting in minimal residual leukemia and relapse. Methods and Results: We designed a novel peptide(E5) that targets CXCR4 and inhibits CXCL12- and stroma-induced adhesion and migration in multiple AML cell lines, displaying anti-AML activity. Mechanistic studies demonstrate that E5 down-regulates CXCL12-induced phosphorylation of Akt, Erk and p38, affecting the cytoskeleton F-actin organization and ultimately resulting in the inhibition of the AML cells responses. We further presented E5's capacity of enhancing the therapeutic efficiency of various chemotherapeutics on AML in vitro and in vivo. Results show that E5 diminished bone marrow stromal cell-provided protection to leukemia cells, significantly increasing the apoptosis induced by chemotherapeutics in AML cells. In an AML mouse xenograft model, E5 induced 1.84-fold increase of circulating AML cells out of protective stroma niche. Combined with vincristine or cyclophosphamide, E5 inhibited infiltration of AML cells into bone marrow, liver and spleen, as well as prolonged the lifespan of AML mice compared with mice treated with chemotherapy alone. In addition, E5 presented no toxicity in vivo.Conclusion: We demonstrated the effect of E5 in inhibiting AML cells from responding to CXCL12- or MS-5 induced activation and eradicating leukemia cells in vitro and in vivo. Furthermore, E5 can reduce tumor burden, significantly improve the efficiency of chemotherapies for AML and extend survival in AML mice.
引文
1.Li X,Guo H,Yang Y,Meng J,Liu J,Wang C,Xu H.Sci Rep.2014;4:6610.
2 .Li X,Guo H,Duan H,Yang Y,Meng J,Liu J,Wang C,Xu H.Sci Rep.2015 Nov 5;5:16228.
2 .Li X,Guo H,Duan H,Yang Y,Meng J,Liu J,Wang C,Xu H.Sci Rep.2015 Nov 5;5:16228.