A general covalent binding model between cytotoxic selenocompounds and albumin revealed by mass spectrometry and X-ray absorption spectroscopy
Zheng, Wenyi (Karolinska University Hospital and Karolinska Institutet (Suècia))
He, Rui (Karolinska University Hospital and Karolinska Institutet (Suècia))
Boada, Roberto (Universitat Autònoma de Barcelona. Departament de Química)
Subirana, Maria Angels (Universitat Autònoma de Barcelona. Departament de Química)
Ginman, Tobias (Sprint Bioscience)
Ottosson, Håkan (Karolinska Institutet (Estocolm, Suècia))
Valiente, Manuel (Universitat Autònoma de Barcelona. Departament de Química)
Zhao, Ying (Karolinska University Hospital and Karolinska Institutet (Suècia))
Hassan, Moustapha (Karolinska University Hospital and Karolinska Institutet (Suècia))

Data:	2020
Resum:	Selenocompounds (SeCs) are promising therapeutic agents for a wide range of diseases including cancer. The treatment results are heterogeneous and dependent on both the chemical species and the concentration of SeCs. Moreover, the mechanisms of action are poorly revealed, which most probably is due to the detection methods where the quantification is based on the total selenium as an element. To understand the mechanisms underlying the heterogeneous cytotoxicity of SeCs and to determine their pharmacokinetics, we investigated selenium speciation of six SeCs representing different categories using liquid chromatography-mass spectrometry (LC-MS) and X-ray absorption spectroscopy (XAS) and the cytotoxicity using leukemic cells. SeCs cytotoxicity was correlated with albumin binding degree as revealed by LC-MS and XAS. Further analysis corroborated the covalent binding between selenol intermediates of SeCs and albumin thiols. On basis of the Se-S model, pharmacokinetic properties of four SeCs were for the first time profiled. In summary, we have shown that cytotoxic SeCs could spontaneously transform into selenol intermediates that immediately react with albumin thiols through Se-S bond. The heterogeneous albumin binding degree may predict the variability in cytotoxicity. The present knowledge will also guide further kinetic and mechanistic investigations in both experimental and clinical settings.
Ajuts:	European Commission 665919 European Commission 778325 Ministerio de Economía y Competitividad CTM2015-65414-C2-1-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer ; Chemical biology ; Chemistry
Publicat a:	Scientific reports, Vol. 10 (January 2020) , art. 1274, ISSN 2045-2322

DOI: 10.1038/s41598-020-57983-y
PMID: 31988319

10 p, 2.1 MB

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