Human serum albumin as a copper source for anticancer thiosemicarbazones
- Author(s)
- Martin Schaier, Enrico Falcone, Tomas Prstek, Bertrand Vileno, Sonja Hager, Bernhard K. Keppler, Petra Heffeter, Gunda Koellensperger, Peter Faller, Christian R. Kowol
- Abstract
Thiosemicarbazones (TSCs) are a class of biologically active compounds with promising anticancer activity. Their typical mechanism, especially of the clinically far developed representative Triapine, is chelation of iron (Fe), with the Fe-containing enzyme ribonucleotide reductase as primary intracellular target. However, for the subclass of terminally disubstituted, nanomolar-Active derivatives like Dp44mT and Me2NNMe2, recent findings suggest that the chelation, stability, and reduction properties of the copper(II) (Cu) complexes are essential for their modes of action. Consequently, it is important to elucidate whether blood serum Cu(II) is a potential metal source for these TSCs. To gain more insights, the interaction of Triapine, Dp44mT or Me2NNMe2 with purified human serum albumin (HSA) as the main pool of labile Cu(II) was investigated by UV-vis and electron paramagnetic resonance measurements. Subsequently, a size-exclusion chromatography inductively coupled plasma mass spectrometry method for the differentiation of Cu species in serum was developed, especially separating the non-labile Cu enzyme ceruloplasmin from HSA. The results indicate that the TSCs specifically chelate copper from the N-Terminal Cu-binding site of HSA. Furthermore, the Cu(II)-TSC complexes were shown to form ternary HSA conjugates, most likely via histidine. Noteworthy, Fe-chelation from transferrin was not overserved, even not for Triapine. In summary, the labile Cu pool of HSA is a potential source for Cu-TSC complex formation and, consequently, distinctly influences the anticancer activity and pharmacological behavior of TSCs.
- Organisation(s)
- Department of Analytical Chemistry, Department of Food Chemistry and Toxicology, Department of Inorganic Chemistry, Mass Spectrometry Centre
- External organisation(s)
- Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research, Université de Strasbourg, University of Vienna
- Journal
- Metallomics
- Volume
- 15
- ISSN
- 1756-5901
- DOI
- https://doi.org/10.1093/mtomcs/mfad046
- Publication date
- 08-2023
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- General Medicine
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/446f9590-d113-4100-923a-9c7cad5f5e3c