Matrine Induces Apoptosis in Human Acute Myeloid Leukemia Cells via the Mitochondrial Pathway and Akt Inactivation

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.

How to Establish Acute Myeloid Leukemia Xenograft Models Using Immunodeficient Mice

“…Conditioning with CTX had often been used in doses 100mg/kg (Rombouts et al, 2000b;Tan et al, 2012), and it had also been used in doses 20mg/kg (Zhang et al, 2012a). The dose of total body irradiation (TBI) depended on the mouse strains and also on the source and irradiator.…”

“…and intravenous (i.v.) routes (Kiser et al, 2001;Zhang et al, 2012a;Zhang et al, 2012b). In recent years, Wang et al (Wang et al, 2012) reported a successful engraftment of human acute lymphoblastic leukemia cells in NOD/SCID mice via intrasplenic inoculation.…”

“…Data accumulated to date suggested that NOG and NSG mice were the best recipients for humanized tissue and human cell engraftment occurred in the following order: NSG or NOG>NSB>NS>SCID (Greiner et al, 1995;Lapidot et al, 1997;Feuring-Buske et al, 2003;Agliano et al, 2008;Snchez et al, 2009). Although NOD/SCID strains had been widely used in recent years, we also considered the SCID mice to be a valuable system for the evaluation of new therapies for AML (Tan et al, 2012;Zhang et al, 2012a). The second factor determining the engraftment potential of human AML was FAB subtypes.…”

Matrine improved the function of heart failure in rats via inhibiting apoptosis and blocking β3-adrenoreceptor/endothelial nitric oxide synthase pathway

“…Matrine was also demonstrated to activate the p38 pathway and trigger caspase-dependent apoptosis by inducing the generation of ROS in non-small cell lung carcinoma (6). Matrine is able to inhibit cell proliferation and induce the apoptosis of acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation (7). Furthermore, the growth of MCF-7 breast cancer cells was also inhibited by matrine via the miR-21/PTEN/Akt pathway (8).…”

Anti-tumor activities of active ingredients in Compound Kushen Injection

“…Matrine can also inhibit cell viability and induce cell apoptosis in human acute myeloid leukemia (AML) cells in a doseand time-dependent manner. After treatment with matrine, apoptosis in AML cells was induced by collapsing the mitochondrial membrane potential, inducing cytochrome c release from mitochondria, reducing the ratio of Bcl-2/Bax, increasing the activation of caspase-3, and decreasing the levels of p-Akt and p-ERK1/2 [20] . In K562 cells, matrine was shown to inhibit cell proliferation and induce apoptosis via the mitochondrial pathway in a time-and dose-dependent manner.…”