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      Matrine reverses the drug resistance of K562/ADM cells to ADM and VCR via promoting autophagy

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          Abstract

          Background

          This study aimed to investigate the effects of matrine (MAT) on the drug resistance of K562/ADM cells.

          Methods

          K562/S and K562/ADM cells were treated with different concentrations of vincristine (VCR), adriamycin (ADM), and/or MAT for 48 h. The cell viability was determined by MTT assay, and the drug-resistant multiple and drug-resistant reversal multiple were calculated based on half-inhibitory concentration (IC50). The cell apoptosis, as well as cell cycle were detected by flow cytometry. The autophagy was evaluated by transmission electron microscope and GFP-LC3 staining. Autophagy-related protein levels of LC3 II, and P62 were detected by Western blot.

          Results

          MAT reduced the viability of K562/S and K562/ADM cells in a dose-dependent manner, and 0.5 mg/mL was identified as the non-cytotoxic concentration. MAT eliminated the drug resistance of K562/ADM cells to ADM and VCR, and the drug resistance reversal multiple was 10.12 and 4.91, respectively. Chloroquine (CQ), a lysosomal inhibitor significantly reversed the inhibitory effect of MAT on the viability of K562/ADM cells. In addition, MAT induced the apoptosis of K562/ADM cells through arresting the cell cycle at G0/G1 phase in a dose-dependent manner. MAT also increased the autophagic vacuoles, the LC3+ punctate fluorescence, as well as the LC3 II protein level, and decreased P62 protein level in K562/ADM cells in a dose-dependent manner.

          Conclusions

          MAT reversed the drug resistance of K562/ADM cells to ADM and VCR through promoting autophagy.

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          Most cited references33

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          Autophagy, a key mechanism of oncogenesis and resistance in leukemia

          Autophagy is a lysosomal pathway involved in degradation of intracellular material. It appears as an adaptation mechanism that is essential for cellular homeostasis in response to various stress conditions. Over the past decade, many studies have linked alteration of autophagy with cancer initiation and progression, autoimmune, inflammatory, metabolic, and degenerative diseases. This review highlights recent findings on the impact of autophagy on leukemic transformation of normal hematopoietic stem cells and summarizes its role on leukemic cell response to chemotherapy.
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            Autophagy: a lysosomal degradation pathway with a central role in health and disease.

            Autophagy delivers cytoplasmic material and organelles to lysosomes for degradation. The formation of autophagosomes is controlled by a specific set of autophagy genes called atg genes. The magnitude of autophagosome formation is tightly regulated by intracellular and extracellular amino acid concentrations and ATP levels via signaling pathways that include the nutrient sensing kinase TOR. Autophagy functions as a stress response that is upregulated by starvation, oxidative stress, or other harmful conditions. Remarkably, autophagy has been shown to possess important housekeeping and quality control functions that contribute to health and longevity. Autophagy plays a role in innate and adaptive immunity, programmed cell death, as well as prevention of cancer, neurodegeneration and aging. In addition, impaired autophagic degradation contributes to the pathogenesis of several human diseases including lysosomal storage disorders and muscle diseases.
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              • Record: found
              • Abstract: found
              • Article: not found
              Is Open Access

              Structural biology of the core autophagy machinery.

              In autophagy, which is an intracellular degradation system that is conserved among eukaryotes, degradation targets are sequestered through the de novo synthesis of a double-membrane organelle, the autophagosome, which delivers them to the lysosomes for degradation. The core autophagy machinery comprising 18 autophagy-related (Atg) proteins in yeast plays an essential role in autophagosome formation; however, the molecular role of each Atg factor and the mechanism of autophagosome formation remain elusive. Recent years have seen remarkable progress in structural biological studies on the core autophagy machinery, opening new avenues for autophagy research. This review summarizes recent advances in structural biological and mechanistic studies on the core autophagy machinery and discusses the molecular mechanisms of autophagosome formation.
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                Author and article information

                Journal
                Transl Cancer Res
                Transl Cancer Res
                TCR
                Translational Cancer Research
                AME Publishing Company
                2218-676X
                2219-6803
                February 2020
                February 2020
                : 9
                : 2
                : 786-794
                Affiliations
                [1]deptDepartment of Hematology , Qilu Hospital of Shandong University (Qingdao) , Qingdao 266035, China
                Author notes

                Contributions: (I) Conception and design: Z Li, N Wang; (II) Administrative support: Z Li; (III) Provision of study materials or patients: Z Li, N Wang; (IV) Collection and assembly of data: T Yue; (V) Data analysis and interpretation: Z Li, N Wang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                Correspondence to: Lu Liu. Department of Hematology, Qilu Hospital of Shandong University (Qingdao), No. 758, Hefei Road, Shibei District, Qingdao 266035, China. Email: liulu2350@ 123456163.com .
                Article
                tcr-09-02-786
                10.21037/tcr.2019.12.11
                8799069
                267f8b47-a2cd-4d32-b254-3ad878cca963
                2020 Translational Cancer Research. All rights reserved.

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 09 August 2019
                : 23 October 2019
                Categories
                Original Article

                matrine (mat),k562/adm cells,multidrug resistance,autophagy,chemotherapy drugs

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