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A designed peptide targeting CXCR4 displays anti-acute myelocytic leukemia activity in vitro and in vivo.

Li X, Guo H, Yang Y, Meng J, Liu J, Wang C, Xu H - Sci Rep (2014)

Bottom Line: We show that E5 has high affinity to multiple AML cells with high CXCR4 level in a concentration dependent manner.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.

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.

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Related in: MedlinePlus

Inhibitory effect of E5 on the migration of multiple leukemia cell lines in the transwell assay.Leukemia cells were seeded in the upper well. CXCL12 was supplemented in the lower chamber (a) or secreted by MS-5 cells seeded in the lower chamber (b). Data are presented as mean ± SD (n = 3). The * represents significant difference from sample groups to the control group (*: p < 0.05, **: p < 0.01).
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f3: Inhibitory effect of E5 on the migration of multiple leukemia cell lines in the transwell assay.Leukemia cells were seeded in the upper well. CXCL12 was supplemented in the lower chamber (a) or secreted by MS-5 cells seeded in the lower chamber (b). Data are presented as mean ± SD (n = 3). The * represents significant difference from sample groups to the control group (*: p < 0.05, **: p < 0.01).

Mentions: Leukemia cells were treated with E5 prior to be seeded in the upper chamber of the transwell device. As Figure 3a shows, in the absence of CXCL12, random migration of leukemia cells was in relative low levels. When CXCL12 was supplemented in the lower chamber of the transwell device, leukemia cells were enhanced to migrate into the chamber (set as 100% as control), and E5 significantly inhibited this effect in all cell lines tested in a concentration-dependent manner. In addition, the inhibitory effect of E5 is associated with the cell type. Treated with E5 at 0.1, 1.0 or 10 µM, the migration percentage was reduced to 65 ± 9.7%, 61 ± 3.6% or 36 ± 5.7% respectively for HL-60; 76 ± 8.8%, 57 ± 18.5% or 41 ± 11.1% for NB4; 90 ± 5.4%, 76 ± 5.0% or 65 ± 17.8% for THP-1; and 83 ± 11.2%, 77 ± 21.3% or 80 ± 11.3% for U937.


A designed peptide targeting CXCR4 displays anti-acute myelocytic leukemia activity in vitro and in vivo.

Li X, Guo H, Yang Y, Meng J, Liu J, Wang C, Xu H - Sci Rep (2014)

Inhibitory effect of E5 on the migration of multiple leukemia cell lines in the transwell assay.Leukemia cells were seeded in the upper well. CXCL12 was supplemented in the lower chamber (a) or secreted by MS-5 cells seeded in the lower chamber (b). Data are presented as mean ± SD (n = 3). The * represents significant difference from sample groups to the control group (*: p < 0.05, **: p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196105&req=5

f3: Inhibitory effect of E5 on the migration of multiple leukemia cell lines in the transwell assay.Leukemia cells were seeded in the upper well. CXCL12 was supplemented in the lower chamber (a) or secreted by MS-5 cells seeded in the lower chamber (b). Data are presented as mean ± SD (n = 3). The * represents significant difference from sample groups to the control group (*: p < 0.05, **: p < 0.01).
Mentions: Leukemia cells were treated with E5 prior to be seeded in the upper chamber of the transwell device. As Figure 3a shows, in the absence of CXCL12, random migration of leukemia cells was in relative low levels. When CXCL12 was supplemented in the lower chamber of the transwell device, leukemia cells were enhanced to migrate into the chamber (set as 100% as control), and E5 significantly inhibited this effect in all cell lines tested in a concentration-dependent manner. In addition, the inhibitory effect of E5 is associated with the cell type. Treated with E5 at 0.1, 1.0 or 10 µM, the migration percentage was reduced to 65 ± 9.7%, 61 ± 3.6% or 36 ± 5.7% respectively for HL-60; 76 ± 8.8%, 57 ± 18.5% or 41 ± 11.1% for NB4; 90 ± 5.4%, 76 ± 5.0% or 65 ± 17.8% for THP-1; and 83 ± 11.2%, 77 ± 21.3% or 80 ± 11.3% for U937.

Bottom Line: We show that E5 has high affinity to multiple AML cells with high CXCR4 level in a concentration dependent manner.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, P. R. China.

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.

Show MeSH
Related in: MedlinePlus