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.

Inhibition of autophagy enhances the antitumour activity of tigecycline in multiple myeloma

“…After treatment with different concentrations of tigecycline with or without bafilomycin A1 (baf A1), the cells were collected and lysed immediately using RIPA lysis buffer (Beyotime Institute of Biotechnology) supplemented with PMSF and Halt protease and phosphatase inhibitor cocktail (Pierce, Rockford, IL). The protein was boiled for 8 minutes in 1× loading buffer and subjected to Western blot analysis using antibodies against SQSTM1/p62, LC3, p‐mTOR, mTOR, p‐AMPKa, AMPKa, p‐p70S6K, p70S6K, p‐4E‐BP1, 4E‐BP1 or GAPDH as reported previously . The bands were visualized by an enhanced chemiluminescence reagent (Thermo Fisher, Fremont, CA), and the optical densities of the bands were analysed using Image J software (NIH, Bethesda, MD).…”

“…The protein was boiled for 8 minutes in 1× loading buffer and subjected to Western blot analysis using antibodies against SQSTM1/p62, LC3, p-mTOR, mTOR, p-AMPKa, AMPKa, p-p70S6K, p70S6K, p-4E-BP1, 4E-BP1 or GAPDH as reported previously. 19 The bands were visualized by an enhanced chemiluminescence reagent (Thermo Fisher, Fremont, CA), and the optical densities of the bands were analysed using Image J software (NIH, Bethesda, MD). When tumour volume reached approximately 300 mm 3 , the mice were randomized into four groups.…”

Benzene induces haematotoxicity by promoting deacetylation and autophagy

“…A portion of the cytosol is sequestered by a so‐called isolation membrane, formation of a double‐membrane structure called the autophagosome, which subsequently fuses with the lysosome/vacuole . Although physiological levels of autophagy are essential for the maintenance of cellular homeostasis during various stress conditions, excessive or uncontrolled levels of autophagy are able to induce cell death . Therefore, autophagy is a double‐edged sword, which has a protective role against cell death or contributes to autophagic cell death.…”

Muscone ameliorates diabetic peripheral neuropathy through activating AKT/mTOR signalling pathway

“…As a major regulator of mammalian autophagy and apoptosis, mTOR is the central processor and integrator of internal and external signals . The occurrence of autophagy and apoptosis is accompanied by the inhibition of AKT/mTOR signalling pathway . Moreover, studies have shown that muscone can induce phosphorylation of AKT during myocardial infarction in mice .…”