Protection of renal cells from cisplatin toxicity by cell cycle inhibitors.
The optimal use of cisplatin as a chemotherapeutic drug has been limited by its nephrotoxicity. Murine models have been used to study cisplatin-induced acute renal failure. After cisplatin administration, cells of the S3 segment in the renal proximal tubule are especially sensitive and undergo extensive necrosis in vivo. Similarly, cultured proximal tubule cells undergo apoptosis in vitro after cisplatin exposure. We have shown in vivo that kidney cells enter the cell cycle after cisplatin administration but that cell cycle-inhibitory proteins p21 and 14-3-3sigma are also upregulated. These proteins coordinate the cell cycle, and deletion of either of the genes resulted in increased nephrotoxicity in vivo or increased cell death in vitro after exposure to cisplatin. However, it was not known whether cell cycle inhibition before acute renal failure could protect from cisplatin-induced cell death, especially in cells with functional p21 and 14-3-3sigma genes. Using several cell cycle inhibitors, including a p21 adenovirus, and the drugs roscovitine and olomoucine, we have been able to completely protect a mouse kidney proximal tubule cell culture from cisplatin-induced apoptosis. The protection by p21 was independent of an effect on the cell cycle and was likely caused by selective inhibition of caspase-dependent and -independent cell death pathways in the cells.
Price
Peter M
PM
Department of Internal medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. PricePeterM@uams.edu
Safirstein
Robert L
RL
Megyesi
Judit
J
D048948:14-3-3 Proteins; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005092:Exonucleases / Q000378:metabolism; D005095:Exoribonucleases; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D061945:Caspase Inhibitors; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D011687:Purines; D016159:Tumor Suppressor Protein p53; D000077546:Roscovitine; D011065:Poly(ADP-ribose) Polymerases; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin