Document Detail


Replication-dependent γ-H2AX formation is involved in docetaxel-induced apoptosis in NSCLC A549 cells.
MedLine Citation:
PMID:  20878124     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Docetaxel is a member of the taxane anti-microtubule class of chemotherapeutic agents, which are currently widely used in clinical cancer therapy. However, the anti-tumor mechanisms of docetaxel are not fully understood. Herein we show that docetaxel induces dose-dependent apoptosis in non-small cell lung cancer A549 cells, as detected by Annexin-V positive cells and PARP cleavage, which is via mitochondrial pathway and dependent on caspase-3 activation. Our study on the mechanisms confirms that docetaxel induces dose-dependent accumulation of cells in M phase and acetylation of α-tubulin, marker of tubulin stablization. Furthermore, docetaxel induces replication-dependent γ-H2AX formation which plays a crucial role in docetaxel-triggered apoptosis. The DNA polymerase inhibitor aphidicolin dose-dependently prevents docetaxel-induced γ-H2AX formation, as well as apoptosis. Notably, 0.6 µM APC almost completely blocked docetaxel-induced γ-H2AX formation and apoptosis. In addition, wortmannin pretreatment caused elevated γ-H2AX level, which was accompanied with increased apoptosis. This effect was due to the inhibition of DNA repair process by wortmannin, as down regulation of p21Waf1/Cip1 and DNA repair proteins such as Ku70, Ku80, DNA-PKcs and Rad50, were detected. These data show, for the first time, that the induction of apoptosis by docetaxel requires DNA replication, and replication-mediated DSBs are critical triggers of docetaxel-induced apoptosis.
Authors:
Feng Zhang; Tao Zhang; Yang Qu; Tao Jiang; Yun-Xin Cao; Chen Li; Lei Fan; Qi-Bing Mei
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncology reports     Volume:  24     ISSN:  1791-2431     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-09-29     Completed Date:  2011-02-18     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1297-305     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, PR China.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*,  genetics
Carcinoma, Non-Small-Cell Lung / drug therapy*,  genetics,  pathology
Caspase 3 / genetics,  metabolism
Cell Division / drug effects
DNA Breaks, Double-Stranded
DNA Repair / drug effects
DNA Replication / drug effects
Histones / biosynthesis*,  genetics,  metabolism
Humans
Lung Neoplasms / drug therapy*,  genetics,  metabolism,  pathology
Taxoids / pharmacology*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/H2AFX protein, human; 0/Histones; 0/Taxoids; 15H5577CQD/docetaxel; EC 3.4.22.-/Caspase 3

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