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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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Therapeutic effects of E5 on human acute myelocytic leukemia in immunocompromised mice transplanted with HL-60 cells.NOD/SCID mice were intravenously injected with HL-60 cells (1 × 106 cells per mouse). After 20 days, treatment was started with injection of sterile water, intraperitoneal injection of CTX (36 mg per kg) or subcutaneous injection of E5 (30 mg per kg) twice a week. (a) Survival of mice treated with sterile water, CTX or E5. (b) Relative weight of the mice during treatment.
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f7: Therapeutic effects of E5 on human acute myelocytic leukemia in immunocompromised mice transplanted with HL-60 cells.NOD/SCID mice were intravenously injected with HL-60 cells (1 × 106 cells per mouse). After 20 days, treatment was started with injection of sterile water, intraperitoneal injection of CTX (36 mg per kg) or subcutaneous injection of E5 (30 mg per kg) twice a week. (a) Survival of mice treated with sterile water, CTX or E5. (b) Relative weight of the mice during treatment.

Mentions: Encouraged by the light of results in vitro, we translated our findings into an in vivo system. We injected HL-60 cells into sub-lethally irradiated NOD/SCID mice, allowed the cells to migrate to the bone marrow and to form an enlarged leukemia burden. Eighteen days after the injection, mice showed marked leukemic symptoms including paresis in the rear limbs, ruffled fur, and remarkably hunched posture in reference to mice of healthy control. On day 20 after the transplant, the leukemia mice were randomly divided into 3 groups: control (control, injected subcutaneously with sterile water), CTX (injected intraperitoneally with cyclophosphamide), and E5 (injected subcutaneously with E5). E5 or CTX was administrated to mice twice a week. As shown in Figure 7a, a prolonged survival was observed in those mice that received E5 treatment compared with the survival of CTX group and control group. Additionally, mice received E5 treatment had less reduction in the body weight (Fig. 7b) than those mice that received CTX treatment or in the control group. On day 36 after the transplant, the percentage of HL-60 cells in the leukocytes collected from spleen and bone marrow was analyzed with flow cytometry, which was 57.3% and 92.7% in the spleen and bone marrow respectively, detected by human CD33 expression, confirming the leukemia burden was formed and proving the effect of E5 in anti-acute myelocytic leukemia as well.


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)

Therapeutic effects of E5 on human acute myelocytic leukemia in immunocompromised mice transplanted with HL-60 cells.NOD/SCID mice were intravenously injected with HL-60 cells (1 × 106 cells per mouse). After 20 days, treatment was started with injection of sterile water, intraperitoneal injection of CTX (36 mg per kg) or subcutaneous injection of E5 (30 mg per kg) twice a week. (a) Survival of mice treated with sterile water, CTX or E5. (b) Relative weight of the mice during treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Therapeutic effects of E5 on human acute myelocytic leukemia in immunocompromised mice transplanted with HL-60 cells.NOD/SCID mice were intravenously injected with HL-60 cells (1 × 106 cells per mouse). After 20 days, treatment was started with injection of sterile water, intraperitoneal injection of CTX (36 mg per kg) or subcutaneous injection of E5 (30 mg per kg) twice a week. (a) Survival of mice treated with sterile water, CTX or E5. (b) Relative weight of the mice during treatment.
Mentions: Encouraged by the light of results in vitro, we translated our findings into an in vivo system. We injected HL-60 cells into sub-lethally irradiated NOD/SCID mice, allowed the cells to migrate to the bone marrow and to form an enlarged leukemia burden. Eighteen days after the injection, mice showed marked leukemic symptoms including paresis in the rear limbs, ruffled fur, and remarkably hunched posture in reference to mice of healthy control. On day 20 after the transplant, the leukemia mice were randomly divided into 3 groups: control (control, injected subcutaneously with sterile water), CTX (injected intraperitoneally with cyclophosphamide), and E5 (injected subcutaneously with E5). E5 or CTX was administrated to mice twice a week. As shown in Figure 7a, a prolonged survival was observed in those mice that received E5 treatment compared with the survival of CTX group and control group. Additionally, mice received E5 treatment had less reduction in the body weight (Fig. 7b) than those mice that received CTX treatment or in the control group. On day 36 after the transplant, the percentage of HL-60 cells in the leukocytes collected from spleen and bone marrow was analyzed with flow cytometry, which was 57.3% and 92.7% in the spleen and bone marrow respectively, detected by human CD33 expression, confirming the leukemia burden was formed and proving the effect of E5 in anti-acute myelocytic leukemia as well.

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