Nephrotoxic cell death by diclofenac and meloxicam.
The nephrotoxicity of diclofenac, a non-steroidal anti-inflammatory drug that inhibits both isoforms of cyclooxygenase (COX) has been reported to be fatal to vultures but this was not so with meloxicam which is COX-2 selective. Our study showed that diclofenac was more toxic than meloxicam to both the proximal tubular LLC-PK1 cells and the distal tubular Madin-Darby canine kidney type II (MDCKII) cells, and that LLC-PK1 cells were more susceptible. Exposure of MDCKII cells to meloxicam caused activation of caspase-9/-3 and release of cytochrome c. These observations together with a positive annexin V-FITC staining implicate an intrinsic mitochondrial cell death pathway by apoptosis. Diclofenac-treated MDCKII cells on the other hand showed extensive propidium iodide staining, suggestive of cell death by necrosis. The mode of cell death in LLC-PK1 cells was however less well-defined with positive annexin V-FITC staining but minimal increase in caspase-3 activity alluding to a caspase-independent pathway.
Ng
Lin Eng
LE
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore.
Halliwell
Barry
B
Wong
Kim Ping
KP
D000818:Animals; D017304:Annexin A5 / Q000737:chemistry; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D045304:Cytochromes c / Q000378:metabolism; D004008:Diclofenac / Q000633:toxicity*; D004285:Dogs; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000077239:Meloxicam; D011419:Propidium / Q000737:chemistry; D013194:Staining and Labeling; D013843:Thiazines / Q000633:toxicity*; D013844:Thiazoles / Q000633:toxicity*
D017304:Annexin A5; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004396:Coloring Agents; D016861:Cyclooxygenase Inhibitors; C492760:FITC-annexin A5; D013843:Thiazines; D013844:Thiazoles; D004008:Diclofenac; D011419:Propidium; D045304:Cytochromes c; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D016650:Fluorescein-5-isothiocyanate; D000077239:Meloxicam