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

作者：Rakshit Srabanti; Bagchi Jayashree; Mandal Labanya; Paul Kausik; Ganguly Dipyaman; Bhattacharjee Sandip; Ghosh Monidipa; Biswas Nabendu; Chaudhuri Utpal; Bandyopadhyay Santu^*

来源：Apoptosis, 2009, 14(3): 298-308.

DOI：10.1007/s10495-008-0305-7

• Imatinib
• NAC
• CML
• Apoptosis
• NO

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.
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.
NAC enhances imatinib-induced apoptosis of Bcr-Abl( ) cells by endothelial nitric oxide synthase-mediated production of nitric oxide.

• 出版日期2009-3