期刊
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
卷 142, 期 7, 页码 1449-1459出版社
SPRINGER
DOI: 10.1007/s00432-016-2160-1
关键词
AML; AML1/ETO; HDAC-1; Differentiation
类别
资金
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [G140042]
- Science Fund for Distinguished Young Scholars of Jiangsu province [BK20130024]
- National Science and Technology Major Project [2012ZX09304-001, 2012ZX09103101-050]
- National Natural Science Foundation of China [81300379, 81373449, 81503096]
- Natural Science Foundation of Jiangsu province [BK20140668]
- Program for Changjiang Scholars and Innovative Research Team in University [PCSIRT-IRT1193]
- Huahai Graduate Innovation Fund [CX13B-006HH]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Fundamental Research Funds for the Central Universities [PY2014YX0001, ZL2014YX0034]
AML1/ETO fusion gene is one of disease-causing genes of t(8;21)-positive acute myeloid leukemia (AML). Oroxylin A (OA) has showed anticancer effects on other cancer cells. Here, studies were conducted to determine the antileukemia effect of OA on t(8;21)-positive AML cells in vitro and in vivo. The effects of OA on cell viability of t(8;21)-positive Kasumi-1 and primary AML cells were analyzed by MTT assay. Cell differentiation was examined by NBT reduction assay, flow cytometry analysis for CD11b/CD14, and Giemsa stain. Protein expressions were determined by Western blots. Immunofluorescence assay was used to verify the effect of OA on HDAC-1 expression in vivo. Immunohistochemical staining was applied to evaluate leukemic infiltration of AML-bearing NOD/SCID mice. OA enhanced NBT reduction activity and CD11b/CD14 expression of AML1/ETO-positive AML cells markedly. Results of Giemsa staining also demonstrated that OA could induce the morphologic changes with reduction of nuclear/cytoplasmic ratios, suggesting the cell differentiation induced by OA. Further study showed that OA decreased the expression of fusion protein AML1/ETO and down-regulated HDAC-1 protein levels in vitro and in vivo. Moreover, OA increased the expression of differentiation-related proteins C/EBP alpha and P21. Acetylation levels of histones were also advanced obviously after treatment of OA. In vivo study indicated that OA could prolong the survival of AML-bearing NOD/SCID mice and reduce leukocytic infiltration of the spleen. All these results suggested that OA might be a novel candidate agent for differentiation therapy for AML1/ETO-positive AML and the mechanism required further investigation.
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