title: Involvement of oxidative stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells.
abstract: It is now well accepted that taxol exhibits cytotoxicity and antitumor activity in many human tumors through microtubule stabilization and induction of G2/M cell cycle arrest with final extensive cell apoptosis. Since many anti-cancer agents exert their cytotoxic effects through reactive oxygen species (ROS), we were interested to evaluate whether oxidative stress is involved in taxol-induced cytotoxicity among human leukemia K562 cells. Our results showed that induction of apoptosis was associated with generation of ROS and glutathione (GSH) depletion. The increase in ROS production and apoptosis were both suppressed by antioxidant N-acetyl-l-cysteine (NAC). Moreover, taxol caused an increase in c-Jun NH(2)-terminal kinase (JNK) and p38 activities, two of the well known mediators of the stress activation pathways. Attenuation of JNK expression in the presence of NAC might indicate the modulation of the level of JNK activity by ROS. Furthermore, our data indicated that Bcl-2α was down-regulated in taxol-treated cells and its expression was modulated by ROS and JNK activity. The activities of caspase-9 and -3 were also increased upon treatment with taxol; however, pre-treatment of cells with NAC or JNK inhibitor (SP600125) impeded taxol-mediated caspase activation and apoptosis in K562 cells, suggesting that JNK acts upstream of the caspases. Taken together, these results indicate that taxol induces apoptosis in chronic myelogenous leukemia cells by inducing intracellular oxidative stress and JNK activation pathway.
authors.affiliation: Institute of Biochemistry and Biophysics, PO Box 13145-1384, University of Tehran, Tehran, Iran.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Meshkini
authors.forename: Razieh
authors.initials: R
authors.lastname: Yazdanparast
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004336:Drug Antagonism; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020014:K562 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017239:Paclitaxel / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D013481:Superoxides; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D017239:Paclitaxel; D000111:Acetylcysteine