Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation

Shenghui Zhang; Yan Zhang; Yan Zhuang; Jiajie Wang; Jianqin Ye; Si Zhang; Jianbo Wu; Kang Yu; Yixiang Han

doi:10.1371/journal.pone.0046853

Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation

PLoS One. 2012;7(10):e46853. doi: 10.1371/journal.pone.0046853. Epub 2012 Oct 8.

Authors

Shenghui Zhang¹, Yan Zhang, Yan Zhuang, Jiajie Wang, Jianqin Ye, Si Zhang, Jianbo Wu, Kang Yu, Yixiang Han

Affiliation

¹ Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by a rapid increase in the number of immature myeloid cells in bone marrow. Despite recent advances in the treatment, AML remains an incurable disease. Matrine, a major component extracted from Sophora flavescens Ait, has been demonstrated to exert anticancer effects on various cancer cell lines. However, the effects of matrine on AML remain largely unknown. Here we investigated its anticancer effects and underlying mechanisms on human AML cells in vitro and in vivo. The results showed that matrine inhibited cell viability and induced cell apoptosis in AML cell lines as well as primary AML cells from patients with AML in a dose- and time-dependent manner. Matrine induced apoptosis by collapsing the mitochondrial membrane potential, inducing cytochrome c release from mitochondria, reducing the ratio of Bcl-2/Bax, increasing activation of caspase-3, and decreasing the levels of p-Akt and p-ERK1/2. The apoptotic effects of matrine on AML cells were partially blocked by a caspase-3 inhibitor Z-DEVD-FMK and a PI3K/Akt activator IGF-1, respectively. Matrine potently inhibited in vivo tumor growth following subcutaneous inoculation of HL-60 cells in SCID mice. These findings indicate that matrine can inhibit cell proliferation and induce apoptosis of AML cells and may be a novel effective candidate as chemotherapeutic agent against AML.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alkaloids / pharmacology*
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Caspase 3 / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cytochromes c / metabolism
Cytosol / drug effects
Cytosol / metabolism
Down-Regulation / drug effects
Enzyme Activation / drug effects
Humans
Leukemia, Myeloid, Acute / pathology*
Matrines
Membrane Potential, Mitochondrial / drug effects
Mice
Mitochondria / drug effects*
Mitochondria / metabolism*
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Phosphoproteins / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Quinolizines / pharmacology*
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein / metabolism

Substances

Alkaloids
Antineoplastic Agents
Phosphoproteins
Proto-Oncogene Proteins c-bcl-2
Quinolizines
bcl-2-Associated X Protein
Cytochromes c
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Caspase 3
Matrines

Grants and funding

This work was supported by National Natural Science of Foundation of China (No.81100355), Zhejiang Provincial Natural Science Foundation of China (No. LQ12H08002), and Administration of Traditional Chinese Medicine of Zhejiang Province, China (No.2010ZQ008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.