Apoptosis

, 14:298

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

  • Srabanti Rakshit
  • Jayashree Bagchi
  • Labanya Mandal
  • Kausik Paul
  • Dipyaman Ganguly
  • Sandip Bhattacharjee
  • Monidipa Ghosh
  • Nabendu Biswas
  • Utpal Chaudhuri
  • Santu Bandyopadhyay
Original Paper

DOI: 10.1007/s10495-008-0305-7

Cite this article as:
Rakshit, S., Bagchi, J., Mandal, L. et al. Apoptosis (2009) 14: 298. doi:10.1007/s10495-008-0305-7

Abstract

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 is 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 NAC-mediated 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 synthase-mediated production of nitric oxide.

Keywords

ImatinibNACCMLApoptosisNO

Abbreviations

NAC

N-acetyl cysteine

CML

Chronic myeloid leukemia

NO

Nitric oxide

NOS

Nitric oxide synthase

ROS

Reactive oxygen species

SNP

Sodium nitroprusside

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Srabanti Rakshit
    • 1
    • 2
  • Jayashree Bagchi
    • 1
  • Labanya Mandal
    • 1
  • Kausik Paul
    • 1
  • Dipyaman Ganguly
    • 1
    • 3
  • Sandip Bhattacharjee
    • 1
  • Monidipa Ghosh
    • 1
  • Nabendu Biswas
    • 1
  • Utpal Chaudhuri
    • 4
  • Santu Bandyopadhyay
    • 1
    • 5
  1. 1.The Department of Infectious Diseases & ImmunologyIndian Institute of Chemical BiologyKolkataIndia
  2. 2.Department of BiochemistryIndian Institute of ScienceBangaloreIndia
  3. 3.Michel Gilliet Lab, Department of Immunology, Center for Cancer Immunology ResearchUT MD Anderson Cancer CenterHoustonUSA
  4. 4.The Institute of Hematology and Transfusion MedicineMedical CollegeKolkataIndia
  5. 5.Department of Infectious Diseases & ImmunologyIndian Institute of Chemical BiologyKolkataIndia