Nicotinamide increases the sensitivity of chronic myeloid leukemia cells to doxorubicin via the inhibition of SIRT1. Issue 1 (12th August 2019)

• Record Type: Journal Article
• Authors: Pan, Shan; Leng, Jun; Deng, Xinzhou; Ruan, Honggang; Zhou, Lu; Jamal, Muhammad; Xiao, Ruijing; Xiong, Jie; Yin, Qian; Wu, Yingjie; Wang, Meng; Yuan, Wen; Shao, Liang; Zhang, Qiuping
• Is Part Of: Journal of cellular biochemistry. Volume 121:Issue 1(2020)
• Page Start: 574
• Page End: 586
• Publication Date: 2019-08-12
• Subjects: CML -- DOX -- NAM -- SIRT1; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29303
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: The NAD‐dependent deacetylase Sirtuin 1 (SIRT1) plays a vital role in leukemogenesis. Nicotinamide (NAM) is the principal NAD + precursor and a noncompetitive inhibitor of SIRT1. In our study, we showed that NAM enhanced the sensitivity of chronic myeloid leukemia (CML) to doxorubicin (DOX) via SIRT1. We found that SIRT1 high expression in CML patients was associated with disease progression and drug resistance. Exogenous NAM efficiently repressed the deacetylation activity of SIRT1 and induced the apoptosis of DOX‐resistant K562 cells (K562R) in a dose‐dependent manner. Notably, the combination of NAM and DOX significantly inhibited tumor cell proliferation and induced cell apoptosis. The knockdown of SIRT1 in K562R cells enhanced NAM+DOX‐induced apoptosis. SIRT1 rescue in K562R reduced the NAM+DOX‐induced apoptosis. Mechanistically, the combinatory treatment significantly increased the cleavage of caspase‐3 and PARP in K562R in vitro and in vivo. These results suggest the potential role of NAM in increasing the sensitivity of CML to DOX via the inhibition of SIRT1. Abstract : In summary, NAM sensitized K562 and K562R cells to DOX, which by facilitating the activation of caspase‐3/PARP and SIRT1 inhibition might pave the way for the development of a potential adjunct in the treatment of blast crisis CML patients.