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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | De Graauw, Marjo Verbeek, Fons Stokman, Geurt Yan, Kuan Van De Water, Bob Ramaiahgari, Sreenivasa Price, Leo S. Qin, Yu |
| Description | Author Affiliation: Qin Y ( Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the Netherlands.) |
| Abstract | BACKGROUND AND PURPOSE: Nephrotoxicity is the principal dose-limiting factor for cisplatin chemotherapy and is primarily associated with proximal tubular epithelial cells, including disruption of cell adhesions and induction of apoptosis. Cell adhesion and survival is regulated by, amongst other factors, the small GTPase Rap and its activator, the exchange protein directly activated by cAMP (Epac). Epac is particularly enriched in renal tubule epithelium. This study investigates the cytoprotective effects of cAMP-Epac-Rap signalling in a model of cisplatin-induced renal cell injury. EXPERIMENTAL APPROACH: The Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP was used to activate the Epac-Rap signalling pathway in proximal tubular epithelial cells. Cells were exposed to cisplatin, in the presence or absence of 8-pCPT-2'-O-Me-cAMP, and nephrotoxicity was determined by monitoring cell-cell junctions and cell apoptosis. KEY RESULTS: Activation of Epac-Rap signalling preserves cell-cell junctions and protects against cell apoptosis of mouse proximal tubular cells during cisplatin treatment. Activation with the Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP or receptor-mediated induction of cAMP both induced cytoprotection against cisplatin, whereas a PKA-selective cAMP analogue was not cytoprotective. 8-pCPT-2'-O-Me-cAMP mediated cytoprotection was blocked by RNAi-mediated silencing of Epac-Rap signalling in these cells. In contrast, 8-pCPT-2'-O-Me-cAMP did not protect against cisplatin-induced cell death of cancer cells that lacked Epac1 expression. CONCLUSIONS AND IMPLICATIONS: Our study identifies activation of Epac-Rap signalling as a potential strategy for reducing the nephrotoxicity associated with cisplatin treatments and, as a result, broadens the therapeutic window of this chemotherapeutic agent. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4b |
| Volume Number | 165 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2012-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Antineoplastic Agents Pharmacology Apoptosis Cisplatin Cyclic AMP Metabolism Guanine Nucleotide Exchange Factors Kidney Tubules, Proximal Animals Drug Effects Caspase 3 Cell Line Cell Line, Tumor Analogs & Derivatives Epithelial Cells Genetics Cytology Membrane Proteins Mice Mice, Inbred C57BL Phosphoproteins RNA, Messenger RNA, Small Interfering Signal Transduction Zonula Occludens-1 Protein Beta Catenin Rap1 GTP-Binding Proteins Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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