ArticleThe Journal of biological chemistry2014
The anticancer agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes prosurvival autophagy by two mechanisms: persistent induction of autophagosome synthesis and impairment of lysosomal integrity.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 71 citations in OpenAlex.
- Evolution of Thiosemicarbazones: From First- to Second-Generation Metal Chelators and Their Reactive Oxygen Species-Mediated Effects in Melanoma.ChemistryOpen · 2026Review
- Iron and metabolic rewiring in cancer.Oncogenesis · 2026Review
- Hypoxia-inducible factor 3α1 increases epithelial-to-mesenchymal transition and iron uptake to drive colorectal cancer liver metastasis.British journal of cancer · 2024Article
- NDRG1 acts as an oncogene in triple-negative breast cancer and its loss sensitizes cells to mitochondrial iron chelation.Frontiers in pharmacology · 2024Article
- A crosstalk between autophagy and apoptosis in intracerebral hemorrhage.Frontiers in cellular neuroscience · 2024Review
- Novel Iron Chelator SK4 Drives Cytotoxicity through Inhibiting Mitochondrial Metabolism in Ovarian and Triple Negative Breast Cancer Cell Lines.Biomedicines · 2023Article
- Autophagy Regulation Using Multimodal Chlorin e6-Loaded Polysilsesquioxane Nanoparticles to Improve Photodynamic Therapy.Pharmaceutics · 2023Article
- Thiosemicarbazones and selected tyrosine kinase inhibitors synergize in pediatric solid tumors: NDRG1 upregulation and impaired prosurvival signaling in neuroblastoma cells.Frontiers in pharmacology · 2022Article
- Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance.Biomedicines · 2021Review
- Article
- Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress.International journal of molecular sciences · 2020Article
- Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma.Cellular oncology (Dordrecht, Netherlands) · 2020Article
- Molecular mechanisms of apoptosis induction in K562 and KG1a leukemia cells by a water-soluble copper(II) thiosemicarbazone complex.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2020Article
- Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor.Angewandte Chemie (International ed. in English) · 2020Article
- Synergistic inhibition of tumor cell proliferation by metformin and mito-metformin in the presence of iron chelators.Oncotarget · 2019Article
- Effects of Ferroportin-Mediated Iron Depletion in Cells Representative of Different Histological Subtypes of Prostate Cancer.Antioxidants & redox signaling · 2019Article
- Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors.Viruses · 2017Review
- Combination of Fe/Cu -chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer.Oncotarget · 2017Article
- The novel thiosemicarbazone, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), inhibits neuroblastoma growth in vitro and in vivo via multiple mechanisms.Journal of hematology & oncology · 2016Article
- A novel copper(II) complex identified as a potent drug against colorectal and breast cancer cells and as a poison inhibitor for human topoisomerase IIα.Inorganic chemistry communications · 2016Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anticancer agents. The selective antitumor and antimetastatic chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) causes lysosomal membrane permeabilization and cell death. Considering the integral role of lysosomes in autophagy and cell death, it was important to assess the effect of Dp44mT on autophagy to further understand its mechanism of action. Notably, Dp44mT affected autophagy by two mechanisms. First, concurrent with its antiproliferative activity, Dp44mT increased the expression of the classical autophagic marker LC3-II as a result of induced autophagosome synthesis. Second, this effect was supplemented by a reduction in autophagosome degradation as shown by the accumulation of the autophagic substrate and receptor p62. Conversely, the classical iron chelator desferrioxamine induced autophagosome accumulation only by inhibiting autophagosome degradation. The formation of redox-active iron or copper Dp44mT complexes was critical for its dual effect on autophagy. The cytoprotective antioxidant N-acetylcysteine inhibited Dp44mT-induced autophagosome synthesis and p62 accumulation. Importantly, Dp44mT inhibited autophagosome degradation via lysosomal disruption. This effect prevented the fusion of lysosomes with autophagosomes to form autolysosomes, which is crucial for the completion of the autophagic process. The antiproliferative activity of Dp44mT was suppressed by Beclin1 and ATG5 silencing, indicating the role of persistent autophagosome synthesis in Dp44mT-induced cell death. These studies demonstrate that Dp44mT can overcome the prosurvival activity of autophagy in cancer cells by utilizing this process to potentiate cell death.
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