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N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide

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Title N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+
cells by endothelial nitric oxide synthase-mediated production
of nitric oxide
 
Creator Rakshit, Srabanti
Bagchi, Jayashree
Mandal, Labanya
Paul, Kausik
Ganguly, Dipyaman
Bhattacharjee, Sandip
Ghosh, Monidipa
Biswas, Nabendu
Chaudhuri, Utpal
Bandyopadhyay, Santu
 
Subject Infectious Diseases and Immunology
 
Description Introduction Imatinib, a small-molecule inhibitor of the
Bcr-Abl kinase, is a successful drug for treating chronic
myeloid leukemia (CML). Bcr-Abl kinase stimulates the
production of H2O2, which in turn activates Abl kinase. We
therefore evaluated whether N-acetyl cysteine (NAC), a
ROS scavenger improves imatinib efficacy.
Materials and methods Effects of imatinib and NAC
either alone or in combination were assessed on Bcr-Abl?
cells to measure apoptosis. Role of nitric oxide (NO) in
NAC-induced enhanced cytotoxicity was assessed using
pharmacological inhibitors and siRNAs of nitric oxide
synthase isoforms. We report that imatinib-induced apoptosis
of imatinib-resistant and imatinib-sensitive Bcr-Abl?
CML cell lines and primary cells from CML patients significantly enhanced by co-treatment with NAC compared
to imatinib treatment alone. In contrast, another ROS
scavenger glutathione reversed imatinib-mediated killing.
NAC-mediated enhanced killing correlated with cleavage
of caspases, PARP and up-regulation and down regulation
of pro- and anti-apoptotic family of proteins, respectively.
Co-treatment with NAC leads to enhanced production
of nitric oxide (NO) by endothelial nitric oxide synthase
(eNOS). Involvement of eNOS dependent NO in NACmediated
enhancement of imatinib-induced cell death was
confirmed by nitric oxide synthase (NOS) specific pharmacological
inhibitors and siRNAs. Indeed, NO donor
sodium nitroprusside (SNP) also enhanced imatinib-mediated
apoptosis of Bcr-Abl? cells.
Conclusion NAC enhances imatinib-induced apoptosis
of Bcr-Abl? cells by endothelial nitric oxide synthasemediated
production of nitric oxide.
 
Date 2009
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/132/1/APOPTOSIS%2C14(3)%2C298%2D308%2C2009[98].pdf
Rakshit, Srabanti and Bagchi, Jayashree and Mandal, Labanya and Paul, Kausik and Ganguly, Dipyaman and Bhattacharjee, Sandip and Ghosh, Monidipa and Biswas, Nabendu and Chaudhuri, Utpal and Bandyopadhyay, Santu (2009) N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide. Apoptosis, 14. pp. 298-308.
 
Relation http://dx.doi.org/10.1007/s10495-008-0305-7
http://www.eprints.iicb.res.in/132/