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      Homoharringtonine Exerts an Antimyeloma Effect by Promoting Excess Parkin-Dependent Mitophagy

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          Homoharringtonine (HHT) has been used as an antileukemia agent in the clinic which processes a high-potential therapeutic efficacy against multiple myeloma (MM). In this study, we investigated the antimyeloma mechanism of HHT.


          Three MM cell lines and a xenograft model were applied. Mitochondrial function was evaluated by detecting MitoTracker Green, the mtDNA copy number, mitochondrial protein and enzyme activity, the mitochondrial membrane potential and mitochondrial morphology. Mitophagy levels were assessed by monitoring autophagosomes, performing a colocalization analysis and determining the levels of related proteins. An shRNA was applied to knockdown Parkin.


          Based on the results of the in vitro experiments, HHT exerted a promising antiproliferative effect on the MM.1S, RPMI 8226 and H929 cell lines by increasing mitophagy. In addition, HHT markedly inhibited myeloma tumor growth and prolonged survival by promoting mitophagy in vivo. Furthermore, HHT treatment contributed to notable mitochondrial dysfunction and Parkin-dependent mitophagy, as evidenced by the destruction of mitochondria, the decrease in the mtDNA copy number, decrease in the Bcl-2/Bax ratio, and decrease in the levels of mitochondrial proteins and the optimal expression of Parkin and NDP52. However, the addition of rapamycin did not produce significant synergistic effect with HHT, indicating that HHT reached the threshold level to induce mitophagy. The colocalization analysis and assessment of mitochondrial function examination further confirmed that HHT triggered mitophagy and mitochondrial dysfunction. Moreover, the antiproliferative effect of HHT was reversed by an shRNA targeting Parkin, highlighting the indispensable role of Parkin-dependent mitophagy in the antimyeloma effect of HHT.


          HHT exerts an antimyeloma effect by inducing excess mitophagy, providing new mechanistic insights into a therapeutic strategy for MM.

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          Most cited references 41

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          Mechanisms of mitophagy.

          Autophagy not only recycles intracellular components to compensate for nutrient deprivation but also selectively eliminates organelles to regulate their number and maintain quality control. Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, mediated by autophagy-related 32 (Atg32), and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L). Moreover, mitophagy is regulated in many metazoan cell types by parkin and PTEN-induced putative kinase protein 1 (PINK1), and mutations in the genes encoding these proteins have been linked to forms of Parkinson's disease.
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            Autophagy pathway: Cellular and molecular mechanisms

            Macroautophagy/autophagy is an essential, conserved self-eating process that cells perform to allow degradation of intracellular components, including soluble proteins, aggregated proteins, organelles, macromolecular complexes, and foreign bodies. The process requires formation of a double-membrane structure containing the sequestered cytoplasmic material, the autophagosome, that ultimately fuses with the lysosome. This review will define this process and the cellular pathways required, from the formation of the double membrane to the fusion with lysosomes in molecular terms, and in particular highlight the recent progress in our understanding of this complex process.
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              Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control.

              Mitochondria, which convert energy for the cell, accumulate damage with age, and the resulting mitochondrial dysfunction has been linked to the development of degenerative diseases and aging. To curb the accumulation of damaged mitochondria, the cell has elaborated a number of mitochondrial quality control processes. We describe recent work suggesting that Parkin and PTEN-induced putative kinase 1 (PINK1), two gene products linked to familial forms of parkinsonism, may constitute one of the cell's mitochondrial quality control pathways-identifying impaired mitochondria and selectively trimming them from the mitochondrial network by mitophagy. In particular, we discuss the regulation of PINK1 protein expression and Parkin localization by the bioenergetic status of individual mitochondria; the mechanism by which PINK1 recruits Parkin to the outer mitochondrial membrane; and Parkin's promotion of mitophagy through its ubiquitination of outer mitochondrial membrane proteins. This recent work suggests that Parkin and PINK1 may be among the first mammalian proteins identified with a direct role in regulating mitophagy, and implicate a failure of mitophagy in the pathogenesis of Parkinson's disease.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                05 November 2020
                : 14
                : 4749-4763
                [1 ]Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine , Jinan, People’s Republic of China
                [2 ]Clinical Laboratory Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, People’s Republic of China
                [3 ]Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, People’s Republic of China
                Author notes
                Correspondence: Xing Cui Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, Shandong Province250014, People’s Republic of ChinaTel/Fax +86 68616042 Email cdz45@foxmail.com
                © 2020 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, References: 41, Pages: 15
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: Taishan Scholar Program;
                Funded by: Key Technology Research and Development Program of Shandong;
                The study was supported by the National Natural Science Foundation of China (No.81774080), the Taishan Scholar Program (No. tsqn201812145) and the Key Technology Research and Development Program of Shandong (No.2019GSF108162).
                Original Research


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