Dual Role of Mitophagy in Cancer Drug Resistance

Yan, Chen; Li, Tao‐Sheng

doi:10.21873/anticanres.12266

Cited by 56 publications

(51 citation statements)

References 33 publications

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“…Mitophagy occurs at a low, basal level in all cells to orchestrate homeostasis of mitochondria biogenesis and degradation. [[qv: 8b,9]] Mitophagy is also involved in developmental processes that require mitochondrial clearance; impairment of mitophagy drastically alters mitochondrial function and cell fate in many cell types 15. Although augmented autophagic flux was identified during osteoblast differentiation and mineral nodule formation,16 the basis in which osteogenic differentiation is modulated by autophagy is unclear.…”

Section: Resultsmentioning

confidence: 99%

Contribution of Mitophagy to Cell‐Mediated Mineralization: Revisiting a 50‐Year‐Old Conundrum

et al. 2018

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Biomineralization in vertebrates is initiated via amorphous calcium phosphate (ACP) precursors. These precursors infiltrate the extracellular collagen matrix where they undergo phase transformation into intrafibrillar carbonated apatite. Although it is well established that ACP precursors are released from intracellular vesicles through exocytosis, an unsolved enigma in this cell‐mediated mineralization process is how ACP precursors, initially produced in the mitochondria, are translocated to the intracellular vesicles. The present study proposes that mitophagy provides the mechanism for transfer of ACP precursors from the dysfunctioned mitochondria to autophagosomes, which, upon fusion with lysosomes, become autolysosomes where the mitochondrial ACP precursors coalesce to form larger intravesicular granules, prior to their release into the extracellular matrix. Apart from endowing the mitochondria with the function of ACP delivery through mitophagy, the present results indicate that mitophagy, triggered upon intramitochondrial ACP accumulation in osteogenic lineage‐committed mesenchymal stem cells, participates in the biomineralization process through the BMP/Smad signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Contribution of Mitophagy to Cell‐Mediated Mineralization: Revisiting a 50‐Year‐Old Conundrum

et al. 2018

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“…On the other hand, excessive mitochondrial clearance may induce metabolic disorders and cell death (259). Therefore, mitophagy likely plays a dual role in cancer drug resistance (260). Mitophagy inhibition enhances the sensitivity of breast cancer cells to classical paclitaxel (114).…”

Section: Targeting Mitochondria Metabolismmentioning

confidence: 99%

Metabolic Plasticity in Chemotherapy Resistance

et al. 2020

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Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance.

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“…Cancers with increasing incidence and mortality have been the leading cause of death, seriously threating the public health and making the design and discovery of chemotherapeutic agents particularly important (Evans et al, 2017). Although substantial progress has been made in the antitumor drugs, drug resistance and high toxicity limit their clinical application (Hughes and Andersson, 2015;Yan and Li, 2018;Santiago-O'farrill et al, 2019). In addition, various factors are involved the development of the tumorigenesis, especially the changes in gene expression associated with mutation, loss, and rearrangement, making the mechanism much more complicated (Wenbo and Wang, 2017).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

Wang

Liu

et al. 2020

Front. Chem.

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Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds a6, a9, a10, b8, and b9 exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds a9 and b8 on Hela's cytostatic activity (a9: IC 50 = 11.15 ± 3.24 µM; b8: IC 50 = 13.68 ± 1.31 µM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound a9 had a certain broad-spectrum inhibitory activity, while compound b8 had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds a9 and b8 in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.

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Dual Role of Mitophagy in Cancer Drug Resistance

Cited by 56 publications

References 33 publications

Contribution of Mitophagy to Cell‐Mediated Mineralization: Revisiting a 50‐Year‐Old Conundrum

Contribution of Mitophagy to Cell‐Mediated Mineralization: Revisiting a 50‐Year‐Old Conundrum

Metabolic Plasticity in Chemotherapy Resistance

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

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