Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia
Abstract Background Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeti...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12967-018-1421-y |
| _version_ | 1818282003173212160 |
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| author | Manman Deng Jie Zha Zhiwu Jiang Xian Jia Yuanfei Shi Peng Li Xiao Lei Chen Zhihong Fang Zhiqiang Du Bing Xu |
| author_facet | Manman Deng Jie Zha Zhiwu Jiang Xian Jia Yuanfei Shi Peng Li Xiao Lei Chen Zhihong Fang Zhiqiang Du Bing Xu |
| author_sort | Manman Deng |
| collection | DOAJ |
| description | Abstract Background Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti-angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells. Method ALL cell lines were treated with different concentration of Apatinib and then CCK8 assay, flow cytometry were used to determine the IC50 value and cell apoptosis, respectively. The effect of Apatinib against primary ALL cells from 11 adult patients and normal counterparts were also analyzed by apoptosis with flow cytometry. Next, we used western bolting and mass cytometry (CyTOF) assay to explore the underlying mechanism of the cytotoxicity of Apatinib. Finally, the anti-leukemia activity was further evaluated in an in vivo xenograft model of ALL. Results Our results showed that Apatinib significantly inhibited cell growth and promoted apoptosis in both B and T lineage ALL cell lines in a dose- and time-dependent manner. The IC50 values of Apatinib against Nalm6, Reh, Jurkat and Molt4 for 48 h were 55.76 ± 13.19, 51.53 ± 10.74, 32.43 ± 5.58, 39.91 ± 9.88 μmol/L, and for 72 h were 30.34 ± 2.65, 31.96 ± 3.92, 17.62 ± 5.90, and 17.65 ± 2.17 μmol/L respectively. Similarly, Apatinib shows cytotoxic activity against primary adult ALL cells while sparing their normal counterparts in vitro. Moreover, Apatinib suppressed ALL growth and progression in an in vivo xenograft model. Mechanistically, Apatinib-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including the PI3 K, MAPK and STAT3 pathways. Conclusion Our study indicates that Apatinib exerts its anti-leukemia effect by inducing apoptosis through suppressing the VEGFR2 signaling pathway, supporting a potential role for Apatinib in the treatment of ALL. |
| first_indexed | 2024-12-13T00:14:06Z |
| format | Article |
| id | doaj.art-99b256612a4c469c89614e297c2c4471 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-13T00:14:06Z |
| publishDate | 2018-02-01 |
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| series | Journal of Translational Medicine |
| spelling | doaj.art-99b256612a4c469c89614e297c2c44712022-12-22T00:05:51ZengBMCJournal of Translational Medicine1479-58762018-02-0116111010.1186/s12967-018-1421-yApatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemiaManman Deng0Jie Zha1Zhiwu Jiang2Xian Jia3Yuanfei Shi4Peng Li5Xiao Lei Chen6Zhihong Fang7Zhiqiang Du8Bing Xu9Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen UniversityKey Laboratory of Regenerative Biology, Southern China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signalling Network, School of Life Sciences, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen UniversityKey Laboratory of Regenerative Biology, Southern China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesState Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signalling Network, School of Life Sciences, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen UniversityDepartment of Translational Science, Amgen Asia R&D CenterDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen UniversityAbstract Background Acute lymphoblastic leukemia (ALL) is a clonal malignant disorder characterized by an uncontrolled proliferation of immature B or T lymphocytes. Extensive studies have suggested an involvement of angiogenesis signaling in ALL progression and resistance to treatment. Thus, targeting angiogenesis with anti-angiogenic drugs may be a promising approach for ALL treatment. In this study, we investigated the effectiveness of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2 in ALL cells. Method ALL cell lines were treated with different concentration of Apatinib and then CCK8 assay, flow cytometry were used to determine the IC50 value and cell apoptosis, respectively. The effect of Apatinib against primary ALL cells from 11 adult patients and normal counterparts were also analyzed by apoptosis with flow cytometry. Next, we used western bolting and mass cytometry (CyTOF) assay to explore the underlying mechanism of the cytotoxicity of Apatinib. Finally, the anti-leukemia activity was further evaluated in an in vivo xenograft model of ALL. Results Our results showed that Apatinib significantly inhibited cell growth and promoted apoptosis in both B and T lineage ALL cell lines in a dose- and time-dependent manner. The IC50 values of Apatinib against Nalm6, Reh, Jurkat and Molt4 for 48 h were 55.76 ± 13.19, 51.53 ± 10.74, 32.43 ± 5.58, 39.91 ± 9.88 μmol/L, and for 72 h were 30.34 ± 2.65, 31.96 ± 3.92, 17.62 ± 5.90, and 17.65 ± 2.17 μmol/L respectively. Similarly, Apatinib shows cytotoxic activity against primary adult ALL cells while sparing their normal counterparts in vitro. Moreover, Apatinib suppressed ALL growth and progression in an in vivo xenograft model. Mechanistically, Apatinib-induced cytotoxicity was closely associated with inhibition of VEGFR2 and its downstream signaling cascades, including the PI3 K, MAPK and STAT3 pathways. Conclusion Our study indicates that Apatinib exerts its anti-leukemia effect by inducing apoptosis through suppressing the VEGFR2 signaling pathway, supporting a potential role for Apatinib in the treatment of ALL.http://link.springer.com/article/10.1186/s12967-018-1421-yApatinibAcute lymphoblastic leukemiaVEGFR2Leukemia therapyAnti-angiogenic agent |
| spellingShingle | Manman Deng Jie Zha Zhiwu Jiang Xian Jia Yuanfei Shi Peng Li Xiao Lei Chen Zhihong Fang Zhiqiang Du Bing Xu Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia Journal of Translational Medicine Apatinib Acute lymphoblastic leukemia VEGFR2 Leukemia therapy Anti-angiogenic agent |
| title | Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia |
| title_full | Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia |
| title_fullStr | Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia |
| title_full_unstemmed | Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia |
| title_short | Apatinib exhibits anti-leukemia activity in preclinical models of acute lymphoblastic leukemia |
| title_sort | apatinib exhibits anti leukemia activity in preclinical models of acute lymphoblastic leukemia |
| topic | Apatinib Acute lymphoblastic leukemia VEGFR2 Leukemia therapy Anti-angiogenic agent |
| url | http://link.springer.com/article/10.1186/s12967-018-1421-y |
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