In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-11-21)
Abstract:
We have recently demonstrated that riboflavin ( Rf ) functions as unconventional bioorthogonal photocatalyst for the activation of Pt IV prodrugs. In this study, we show how the combination of light and Rf with two Pt IV 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(NH 3 ) 2 (Cl) 2 (O 2 CCH 2 CH 2 CO 2 H) 2 ] ( 1 ) and cis , cis , trans -[Pt(NH 3 ) 2 (CBDCA)(O 2 CCH 2 CH 2 CO 2 H) 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. 195 Pt 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 H 2 AX 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 pH 2 AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system.
Type of Medium:
Online Resource
ISSN:
2045-2322
DOI:
10.1038/s41598-018-35655-2
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2018
detail.hit.zdb_id:
2615211-3
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