ET-18-OCH(3)-induced cytotoxicity and DNA damage in rat astrocytes.
The ether lipid 1-octadecyl-2-methyl-rac-glicero-3-phosphocholine (ET-18-OCH(3)) is known to be selectively cytotoxic toward several types of tumor cells, in which it seems to activate a process of apoptotic cell death. Moreover, the drug has been demonstrated to be active in normal cells too, particularly in rat astrocytes. In these cells at low dosage (from 1 to 6 microg/ml of medium) ET-18-OCH(3) stimulates maturation and protective responses, whereas at increasing dosages (from 8 to 20 microg/ml) it shows cytotoxic effects. The present study demonstrates that when ET-18-OCH(3) is added to astrocytes, it activates, in a time- and concentration-dependent manner, an oxidative process by increasing both the generation of reactive oxygen species (ROS), including nitric oxide, and lipid peroxidation. When there is a high ET-18-OCH(3) concentration or the time of treatment is prolonged, the increased oxidative condition seems to trigger DNA fragmentation (monitored by COMET assay) as well as loss in cell viability. These cytotoxic effects indicate that ROS may be considered, in our experimental model, as executioners of a program of cell death. In addition, ET-18-OCH(3) being a promising molecule in antitumor therapy, our data, while reinforcing the importance of monitoring the therapeutic drug dosage employed, also suggest that it may be useful to associate some antioxidants with antitumor treatments.
Renis
M
M
Institute of Biochemistry, Faculty of Pharmacy, University of Catania, Viale Andrea Doria, 6, 95125, Catania, Italy. renis@mbox.unict.it
Cardile
V
V
Palumbo
M
M
Russo
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020552:Comet Assay; D017077:Culture Media, Conditioned / Q000737:chemistry; D004247:DNA / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009566:Nitrates / Q000032:analysis; D009573:Nitrites / Q000032:analysis; D010742:Phospholipid Ethers / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D009566:Nitrates; D009573:Nitrites; D010742:Phospholipid Ethers; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C026659:edelfosine; C029569:diacetyldichlorofluorescein; D019323:omega-N-Methylarginine; D004247:DNA; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue