ArticleBiochemical pharmacology2014
Distinct mechanisms of cell-kill by triapine and its terminally dimethylated derivative Dp44mT due to a loss or gain of activity of their copper(II) complexes.
Article in Biochemical pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- Synthesis, characterization, crystal structures, antitumor activity, and computational study of novel thiosemicarbazone derivatives from thiazol-2/5-carbaldehyde.RSC advances · 2026Article
- Distinct Effects of Copper Ionophores on Intracellular Copper and Cell Viability in Wild-Type and CTR1-Deficient SH-SY5Y Cells.ACS omega · 2026Article
- Targeting Copper in Cancer: Chelators to Counteract Cuproplasia and Ionophores to Promote Cuproptosis.Journal of medicinal chemistry · 2026Review
- Cuproptosis Inducers in Cancer Therapy: State of the Art and Challenges.Chemical record (New York, N.Y.) · 2026Review
- Article
- Evolution of Thiosemicarbazones: From First- to Second-Generation Metal Chelators and Their Reactive Oxygen Species-Mediated Effects in Melanoma.ChemistryOpen · 2026Review
- Desulfurization of thiosemicarbazones: the role of metal ions and biological implications.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2024Review
- 3-AP inhibits the growth of human osteosarcoma by decreasing the activity of the iron-dependent pathway.Medical oncology (Northwood, London, England) · 2023Article
- Human serum albumin as a copper source for anticancer thiosemicarbazones.Metallomics : integrated biometal science · 2023Article
- Synthesis, Structure, and Biologic Activity of Some Copper, Nickel, Cobalt, and Zinc Complexes with 2-FormylpyridineBioinorganic chemistry and applications · 2022Article
- Liposomal formulations of anticancer copper(II) thiosemicarbazone complexes.Dalton transactions (Cambridge, England : 2003) · 2021Article
- Anemia in Sports: A Narrative Review.Life (Basel, Switzerland) · 2021Review
- Triapine Analogues and Their Copper(II) Complexes: Synthesis, Characterization, Solution Speciation, Redox Activity, Cytotoxicity, and mR2 RNR Inhibition.Inorganic chemistry · 2021Article
- Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance.Biomedicines · 2021Review
- Reversing oncogenic transformation with iron chelation.Oncotarget · 2021Review
- Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux.Journal of medicinal chemistry · 2020Article
- Isoquinoline thiosemicarbazone displays potent anticancer activity withRSC medicinal chemistry · 2020Article
- The thiosemicarbazone MeCell death & disease · 2018Article
- Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity.Oncotarget · 2017Article
- Impact of Stepwise NH2-Methylation of Triapine on the Physicochemical Properties, Anticancer Activity, and Resistance Circumvention.Journal of medicinal chemistry · 2016Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Triapine, currently being evaluated as an antitumor agent in phase II clinical trials, and its terminally dimethylated derivative Dp44mT share the α-pyridyl thiosemicarbazone backbone that functions as ligands for transition metal ions. Yet, Dp44mT is approximately 100-fold more potent than triapine in cytotoxicity assays. The aims of this study were to elucidate the mechanisms underlying their potency disparity and to determine their kinetics of cell-kill in culture to aid in the formulation of their clinical dosing schedules. The addition of Cu(2+) inactivated triapine in a 1:1 stoichiometric fashion, while it potentiated the cytotoxicity of Dp44mT. Clonogenic assays after finite-time drug-exposure revealed that triapine produced cell-kill in two phases, one completed within 20 min that caused limited cell-kill, and the other occurring after 16 h of exposure that produced extensive cell-kill. The ribonucleotide reductase inhibitor triapine at 0.4 μM caused immediate complete arrest of DNA synthesis, whereas Dp44mT at this concentration did not appreciably inhibit DNA synthesis. The inhibition of DNA synthesis by triapine was reversible upon its removal from the medium. Cell death after 16 h exposure to triapine paralleled the appearance of phospho-(γ)H2AX, a marker of DNA double-strand breaks induced by collapse of DNA replication forks after prolonged replication arrest. In contrast to triapine, Dp44mT produced robust cell-kill within 1h in a concentration-dependent manner. The short-term action of both agents was prevented by thiols, indicative of the involvement of reactive oxygen species. The time dependency in the production of cell-kill by triapine should be considered in treatment regimens.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.