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. 2015 Nov 5:5:16228.
doi: 10.1038/srep16228.

Improving chemotherapeutic efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering with CXCR4/CXCL12 axis

Xiaojin Li  1 , Hua Guo  1 , Hongyang Duan  2 , Yanlian Yang  2 , Jie Meng  1 , Jian Liu  1 , Chen Wang  2 , Haiyan Xu  1
Affiliations

Improving chemotherapeutic efficiency in acute myeloid leukemia treatments by chemically synthesized peptide interfering with CXCR4/CXCL12 axis

Xiaojin Li et al. Sci Rep. .

Abstract

Bone marrow stroma can protect acute myeloid leukemia (AML) cells against chemotherapeutic agents and provide anti-apoptosis and chemoresistance signals through secreting chemokine CXCL12 to activate its receptor CXCR4 on AML cells, resulting in minimal residual leukemia and relapse. Therefore disrupting the CXCR4/CXCL12 axis with antagonists is of great significance for improving chemosensitivity and decreasing relapse rate. In a previous study, we reported a novel synthetic peptide E5 with its remarkable effect on inhibiting CXCR4/CXCL12-mediated adhesion and migration of AML cells. Here we presented E5's capacity of enhancing the therapeutic efficiency of various chemotherapeutics on AML in vitro and in vivo. Results showed that E5 can diminish bone marrow stromal cell-provided protection to leukemia cells, significantly increasing the apoptosis induced by various chemotherapeutics in multiple AML cell lines. 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 according to the histological analysis and routine clinical parameters of serum analysis.

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Figures

Figure 1
Figure 1. E5 inhibits MS-5 mediated-protection and sensitizes leukemia cells to different chemotherapies.
(A) E5 enhances vincristine, cisplatin or 10-hydroxy camptothecin-induced apoptosis in HL-60 cells co-cultured with MS-5 cells. HL-60 cells were treated with drugs alone, or drugs in combination with E5 in the absence or presence of MS-5 cells for 48 h. Apoptotic cells were detected by Annexin V flow cytometry. (B) E5 enhances 10-hydroxy camptothecin-induced apoptosis in multiple AML cell lines including NB4, THP-1 and U937 cells co-cultured with MS-5 cells for 48 h. (C) After continuous combination treatment, vincristine drastically reduces HL-60 cell viability. HL-60 cells growing on MS-5 cell layer were treated with vincristine alone or combined with E5 for 10 days and cell viability was detected using trypan blue every day. Data are presented as mean ± SD (n = 3). The * represents significant difference between two groups (*p < 0.05, **p < 0.01).
Figure 2
Figure 2. E5 induces a rapid mobilization of leukemia cells into the peripheral blood.
Peripheral blood samples were collected through tail vein from three E5-monotreated mice before and 4 h after administration of E5. The percentage of CD33 positive cells (HL-60) was detected with flow cytometry.
Figure 3
Figure 3. In vivo combination treatment of AML mice with vincristine (Vin) and E5.
From day 20 of HL-60 transplantation, AML mice received Vin intraperitoneally 4 h after subcutaneous E5 administration twice weekly. (A) Overall survival of AML mice treated with sterile water (n = 5), E5 alone (n = 5), Vin alone (n = 7), or a combination of both (n = 7). (B–D) The percentage of HL-60 cells in the bone marrow, spleen and peripheral blood of AML mice in each group was determined with flow cytometry (n = 4) (*p < 0.05).
Figure 4
Figure 4. In vivo effects of vincristine (Vin) and E5 on infiltration of HL-60 cells into spleen and liver.
(A) The weight and size of spleens in healthy mice (without HL-60 transplantation) and Vin-monotreated or combination treated AML mice. (B) Histologic sections of spleen and liver in each group of mice were stained with H&E. Images of each organ in the second line are the amplification of images in the first line. Red arrows represent normal cells and blue arrows represent HL-60 cells infiltrated in spleens. Yellow arrows represent HL-60 cells infiltrated into livers.
Figure 5
Figure 5. In vivo combination treatment of AML mice with cyclophosphamide (CTX) and E5.
(A) The percentage of CD33 positive cells (HL-60) in the bone marrow, spleen and peripheral blood of AML mice in each group was determined with flow cytometry. Data are presented as mean ± SD (n = 4). The * represents significant difference between two groups (*p < 0.05, **p < 0.01). (B) Wright-stained peripheral blood smears of AML mice in each group. Yellow arrows represent HL-60 cells. Scale bar represents 50 μm. (C) Overall survival of AML mice treated with sterile water, E5 alone, CTX alone, or a combination of both (n = 9). (D) Relative weight of the mice during the period of treatment.
Figure 6
Figure 6. In vivo effects of cyclophosphamide (CTX) and E5 on infiltration of HL-60 cells into spleen and liver.
(A) The weight and size of spleens in healthy mice (without HL-60 transplantation) and CTX-monotreated or combination treated AML mice. (B) Histologic sections of spleen and liver in each group of mice were stained with H&E. Images of each organ in the second line are the amplification of images in the first line. Red arrows represent normal cells and blue arrows represent HL-60 cells infiltrated in spleens. Yellow arrows represent HL-60 cells infiltrated into livers.
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