title: A designed peptide targeting CXCR4 displays anti-acute myelocytic leukemia activity in vitro and in vivo.
abstract: Leukemia cells highly expressing chemokine receptor CXCR4 can actively response to stroma derived factor 1α (CXCL12), trafficking and homing to the marrow microenvironment, which causes poor prognosis and relapse. Here we demonstrate that a novel designed peptide (E5) targeting CXCR4 inhibits CXCL12- and stroma-induced activation in multiple acute myelocytic leukemia (AML) cell lines and displays anti-AML activity. We show that E5 has high affinity to multiple AML cells with high CXCR4 level in a concentration dependent manner. E5 significantly inhibits CXCL12- or murine stromal cell (MS-5)-induced migration of leukemia cells and prevents the cells from adhering to stromal cells. Mechanistic studies demonstrate that E5 down-regulates CXCL12-induced phosphorylation of Akt, Erk, and p38, which affects the cytoskeleton F-actin organization and ultimately results in the inhibition of CXCL12- and stroma-mediated leukemia cell responses. E5 can induce concentration-dependent apoptosis in the four AML cell lines tested while did not affect the viability of MS-5 or human umbilical vein cell (ea.hy926) even at 80 µM, both of which have a low level of CXCR4. In vivo experimental results show that immunocompromised mice transplanted with HL-60 cells survived longer when treated with E5 twice a week in comparison to those treated with cyclophosphamide.
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.affiliation: National Center for Nanoscience and Technology, Beijing 100190, P. R. China.
authors.forename: Yanlian
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: National Center for Nanoscience and Technology, Beijing 100190, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D010455:Peptides / Q000008:administration & dosage*; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C000623221:E5 CXCR4-targeting peptide; D010455:Peptides; D019718:Receptors, CXCR4; D003520:Cyclophosphamide