Biological activity of PtIV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis

Alessio Terenzi, Alessio Terenzi, Bernhard K. Keppler, Walter Berger, Silvia Alonso-De Castro, Bernhard Englinger, Sonja Hager, Adriana Faraone, Javier Calvo Martínez, Luca Salassa, Markus Galanski, Adriana Faraone

Risultato della ricerca: Articlepeer review

8 Citazioni (Scopus)

Abstract

We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) and cis,cis,trans-[Pt(NH3)2(CBDCA)(O2CCH2CH2CO2H)2] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. 195Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf-1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf-mediated photochemical activation. Phosphorylation of H2AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH2AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.
Lingua originaleEnglish
pagine (da-a)1-10
Numero di pagine10
RivistaScientific Reports
Volume8
Stato di pubblicazionePublished - 2018

All Science Journal Classification (ASJC) codes

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