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Oroxylin A, a natural anticancer flavonoid compound, induces differentiation of t(8;21)-positive Kasumi-1 and primary acute myeloid leukemia cells

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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.

Materials and methods

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.

Results

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/EBPα 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.

Conclusions

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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Acknowledgments

This work was supported by the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. G140042), Science Fund for Distinguished Young Scholars of Jiangsu province (BK20130024), the National Science and Technology Major Project (No. 2012ZX09304-001, 2012ZX09103101-050), the National Natural Science Foundation of China (Nos. 81300379, 81373449, and 81503096), Natural Science Foundation of Jiangsu province (No. BK20140668), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT-IRT1193), and Huahai Graduate Innovation Fund (CX13B-006HH), and the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Fundamental Research Funds for the Central Universities (PY2014YX0001; ZL2014YX0034).

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    Authors and Affiliations

    1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, JiangSu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People’s Republic of China

      Hui Hui, Xiaoxiao Zhang, Hui Li, Xiao Liu, Le Shen, Qinglong Guo & Na Lu

    2. Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People’s Republic of China

      Jingyan Xu

    3. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, People’s Republic of China

      Yu Zhu

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    1. Hui Hui
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    Correspondence to Jingyan Xu, Qinglong Guo or Na Lu.

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    Hui Hui and Xiaoxiao Zhang have contributed equally to this work.

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    Hui, H., Zhang, X., Li, H. et al. Oroxylin A, a natural anticancer flavonoid compound, induces differentiation of t(8;21)-positive Kasumi-1 and primary acute myeloid leukemia cells. J Cancer Res Clin Oncol 142, 1449–1459 (2016). https://doi.org/10.1007/s00432-016-2160-1

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