Back to Search
Start Over
High Copper Complex Stability and Slow Reduction Kinetics as Key Parameters for Improved Activity, Paraptosis Induction, and Impact on Drug-Resistant Cells of Anticancer Thiosemicarbazones
- Source :
- Antioxidants & Redox Signaling. 33:395-414
- Publication Year :
- 2020
- Publisher :
- Mary Ann Liebert Inc, 2020.
-
Abstract
- Aims: Due to their significant biological activity, thiosemicarbazones (TSCs) are promising candidates for anticancer therapy. In part, the efficacy of TSCs is linked to their ability to chelate essential metal ions such as copper and iron. Triapine, the best-studied anticancer TSC, has been tested clinically with promising results in hematological diseases. During the past few years, a novel subclass of TSCs with improved anticancer activity was found to induce paraptosis, a recently characterized form of cell death. The aim of this study was to identify structural and chemical properties associated with anticancer activity and paraptosis induction of TSCs. Results: When testing a panel of structurally related TSCs, compounds with nanomolar anticancer activity and paraptosis-inducing properties showed higher copper(II) complex solution stability and a slower reduction rate, which resulted in reduced redox activity. In contrast, TSCs with lower anticancer activity induced higher levels of superoxide that rapidly stimulated superoxide dismutase expression in treated cells, effectively protecting the cells from drug-induced redox stress. Innovation: Consequently, we hypothesize that in the case of close Triapine derivatives, intracellular reduction leads to rapid dissociation of intracellularly formed copper complexes. In contrast, TSCs characterized by highly stable, slowly reducible copper(II) complexes are able to reach new intracellular targets such as the endoplasmic reticulum-resident protein disulfide isomerase. Conclusion: The additional modes of actions observed with highly active TSC derivatives are based on intracellular formation of stable copper complexes, offering a new approach to combat (drug-resistant) cancer cells.
- Subjects :
- Thiosemicarbazones
0301 basic medicine
Cell Survival
Physiology
Clinical Biochemistry
Antineoplastic Agents
Endoplasmic Reticulum
Biochemistry
Antioxidants
Paraptosis
Superoxide dismutase
03 medical and health sciences
chemistry.chemical_compound
Cell Line, Tumor
Humans
Chelation
Protein disulfide-isomerase
Molecular Biology
General Environmental Science
030102 biochemistry & molecular biology
biology
Superoxide
Biological activity
Cell Biology
Oxidative Stress
030104 developmental biology
Solubility
chemistry
Drug Resistance, Neoplasm
Cancer cell
biology.protein
Biophysics
General Earth and Planetary Sciences
Oxidation-Reduction
Copper
Intracellular
Subjects
Details
- ISSN :
- 15577716 and 15230864
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Antioxidants & Redox Signaling
- Accession number :
- edsair.doi.dedup.....460654471024126af9aabfc492b1e60a