JPET Introducing ALZET?ew Model 2006 Pump

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 1, 2006; DOI: 10.1124/jpet.106.107771

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.106.107771v1
319/2/551    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Probin, V.
Right arrow Articles by Zhou, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Probin, V.
Right arrow Articles by Zhou, D.


Received for publication May 15, 2006.
Revised July 31, 2006.
Accepted for publication July 31, 2006.

BUSULFAN SELECTIVELY INDUCES CELLULAR SENESCENCE BUT NOT APOPTOSIS IN WI38 FIBROBLASTS VIA A P53-INDEPENDENT BUT ERK-P38 MAPK-DEPENDENT MECHANISM

Virginia Probin 1, Yong Wang 1, Aiping Bai 1, Daohong Zhou 1*

1 Medical University of South Carolina

* Address correspondence to: E-mail: zhoud{at}musc.edu

Abstract

Busulfan (BU) is a unique alkylating agent that primarily targets slowly proliferating or non-proliferating cells in the body, leading to various normal tissue damage while killing leukemia cells. However, the mechanism(s) of action whereby BU injures normal cells has not been well defined and therefore, was investigated in the present study by using the normal human diploid WI38 fibroblasts as a model system. We found that WI38 fibroblasts incubated with BU (from 7.5 to 120µM) for 24 h underwent senescence but not apoptosis in a dose-independent manner, whereas cells incubated with 80µM and 20µM etoposide (Etop) committed to apoptosis and senescence, respectively. The induction of WI38 cell senescence by Etop was associated with p53 activation and could be attenuated by down-regulation of p53 using {alpha}-pifithrin ({alpha}-PFT) or p53 small interference RNA (siRNA). In contrast, WI38 cell senescence induced by BU was associated with prolonged activation of extracellular signal-regulated kinase (Erk), p38 mitogen-activated protein kinase (p38) and c-Jun NH2-terminal kinase (JNK), and could be suppressed by the inhibition of Erk and/or p38 with PD98059 and/or SB203580, respectively. However, inhibition of p53 with {alpha}-PFT or p53 siRNA or JNK with SP600125 failed to protect WI38 cells from BU-induced senescence. These findings suggest that BU is a distinctive chemotherapeutic agent that can selectively induce normal human fibroblast senescence through the Erk and p38 pathways.


Key words: alkylating agent, apoptosis, busulfan, p38 MAPK, p53, senescence


This article has been cited by other articles:


Home page
 Molecular Cancer TherapeuticsHome page
A. Katsoulas, Z. Rachid, J. P. McNamee, C. Williams, and B. J. Jean-Claude
Combi-targeting concept: an optimized single-molecule dual-targeting model for the treatment of chronic myelogenous leukemia
Mol. Cancer Ther., May 1, 2008; 7(5): 1033 - 1043.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. H. Heiss, Y. D. C. Schilder, and V. M. Dirsch
Chronic Treatment with Resveratrol Induces Redox Stress- and Ataxia Telangiectasia-mutated (ATM)-dependent Senescence in p53-positive Cancer Cells
J. Biol. Chem., September 14, 2007; 282(37): 26759 - 26766.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.