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research article

Cellular uptake and subcellular distribution of ruthenium-based metallodrugs under clinical investigation versus cisplatin

Groessl, Michael  
•
Zava, Olivier  
•
Dyson, Paul J.  
2011
Metallomics

The cellular uptake and subcellular distribution including adduct formation with genomic DNA and uptake into mitochondria of two ruthenium(III)-based drugs in clinical trials, KP1019 and NAMI-A, and cisplatin, was investigated in cisplatin sensitive and resistant A2780 human ovarian carcinoma cells. These data indicate that reduced metal uptake into mitochondria in combination with increased binding towards low molecular weight components involved in detoxification mechanisms is essential for cisplatin resistance. The ruthenium drugs show distinct differences with respect to cisplatin, especially in the cisplatin resistant cells; in comparison to the sensitive cells, KP1019 exhibits higher cytotoxicity and an only slightly changed metabolism of the drug, whereas NAMI-A treatment results in increased intracellular ruthenium levels and a higher number of ruthenium-DNA adducts. In addition, size exclusion-inductively coupled mass spectrometry indicates that adduct formation with high molecular weight components in the particulate and nuclear fractions is crucial for the therapeutic effect of KP1019 in both cisplatin resistant and sensitive cell lines.

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Type
research article
DOI
10.1039/c0mt00101e
Web of Science ID

WOS:000291350500005

Author(s)
Groessl, Michael  
•
Zava, Olivier  
•
Dyson, Paul J.  
Date Issued

2011

Published in
Metallomics
Volume

3

Start page

591

End page

599

Subjects

Plasma-Mass Spectrometry

•

Ovarian-Cancer Cells

•

Anticancer Metallodrugs

•

Icp-Ms

•

Metal-Compounds

•

Phase-I

•

Platinum

•

Dna

•

Resistance

•

Complexes

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LCOM  
Available on Infoscience
December 16, 2011
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/74017
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