Title: Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics
Authors: WILMES AnjaBIELOW ChrisRANNINGER ChristinaBELLWON PatriciaASCHAUER LydiaLIMONCIEL AliceCHASSAIGNE HubertKRISTL TheresaAICHE StefanHUBER ChristianGUILLOU ClaudeHEWITT PhilipLEONARD MatrinDEKANT WolfgangBOIS FredericJENNINGS Paul
Citation: TOXICOLOGY IN VITRO vol. 30 no. 1, Part A p. 117-127
Publisher: PERGAMON-ELSEVIER SCIENCE LTD
Publication Year: 2014
JRC N°: JRC89760
ISSN: 0887-2333
URI: http://www.sciencedirect.com/science/article/pii/S0887233314001957
http://publications.jrc.ec.europa.eu/repository/handle/JRC89760
DOI: 10.1016/j.tiv.2014.10.006
Type: Articles in periodicals and books
Abstract: Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 lM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity.
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