title: Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells.
abstract: Pharmacological modulation of autophagy has been referred to as a promising therapeutic strategy for cancer. Matrine, a main alkaloid extracted from Sophora flavescens Ait, has antitumour activity against acute myelocytic leukaemia (AML). Whether autophagy is involved in antileukaemia activity of matrine remains unobvious. In this study, we demonstrated that matrine inhibited cell viability and colony formation via inducing apoptosis and autophagy in AML cell lines HL-60, THP-1 and C1498 as well as primary AML cells. Matrine promoted caspase-3 and PARP cleavage dose-dependently. Matrine up-regulated the level of LC3-II and down-regulated the level of SQSTM1/p62 in a dose-dependent way, indicating that autophagy should be implicated in anti-AML effect of matrine. Furthermore, the autophagy inhibitor bafilomycin A1 relieved the cytotoxicity of matrine by blocking the autophagic flux, while the autophagy promoter rapamycin enhanced the cytotoxicity of matrine. Additionally, matrine inhibited the phosphorylation of Akt, mTOR and their downstream substrates p70S6K and 4EBP1, which led to the occurrence of autophagy. In vivo study demonstrated that autophagy was involved in antileukaemia effect of matrine in C57BL/6 mice bearing murine AML cell line C1498, and the survival curves showed that mice did benefit from treatment with matrine. Collectively, our findings indicate that matrine exerts antitumour effect through apoptosis and autophagy, and the latter one might be a potential therapeutic strategy for AML.
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Ruye
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Songfu
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011807:Quinolizines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D000093842:Matrines
chemical_list: D000470:Alkaloids; D011807:Quinolizines; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000093842:Matrines
keywords: Akt; acute myeloid leukaemia; apoptosis; autophagy; mTOR; matrine