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.
Highlights
Acute myeloid leukaemia (AML) is a clonal haematopoietic disorder resulting from multiple genetic and epigenetic lesions affecting differentiation, proliferation and apoptosis [1]
We demonstrated that matrine solely induced both autophagy and apoptosis dose-dependently in AML cells in vitro
To visualize the expression of SQSTM1/p62 and LC3 II, images of bone and spleen were captured using a microscope with CCD
Summary
Acute myeloid leukaemia (AML) is a clonal haematopoietic disorder resulting from multiple genetic and epigenetic lesions affecting differentiation, proliferation and apoptosis [1]. Three main apoptotic pathways identified, including mitochondrial pathway, death receptor pathway and endoplasmic reticulum stress pathway, converge on the executive enzyme caspase-3, and the activation of caspase-3 leads to the activation of poly-ADP-ribose polymerase (PARP) [3]. Another type of cell death named autophagy is often confused with apoptosis. Like SQSTM1/p62, are selectively degraded by autophagy and able to act as cargo receptors to directly interact with autophagosomal marker protein LC3 for efficient selective autophagy [5] Several signalling pathways, such as PI3K/Akt/mTOR/p70S6K pathway, have been demonstrated to be involved in the regulation of autophagy [6,7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
