期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 22, 期 10, 页码 4899-4912出版社
WILEY
DOI: 10.1111/jcmm.13755
关键词
CML; leukaemic stem cell; parthenolide; ROS
资金
- Instituto de Bebidas para la Salud y Bienestar
Tyrosine kinase inhibitors (TKI) have become a first-line treatment for chronic myeloid leuakemia (CML). TKIs efficiently target bulk CML cells; however, they are unable to eliminate the leukaemic stem cell (LSC) population that causes resistance and relapse in CML patients. In this study, we assessed the effects of parthenolide (PTL) and dimethyl amino parthenolide (DMAPT), two potent inhibitors of LSCs in acute myeloid leukaemia (AML), on CML bulk and CML primitive (CD34(+)lin(-)) cells. We found that both agents induced cell death in CML, while having little effect on the equivalent normal hematopoietic cells. PTL and DMAPT caused an increase in reactive oxygen species (ROS) levels and inhibited NF-kappa B activation. PTL and DMAPT inhibited cell proliferation and induced cell cycle arrest in G(0) and G(2) phases. Furthermore, we found cell cycle inhibition to correlate with down-regulation of cyclin D1 and cyclin A. In summary, our study shows that PTL and DMAPT have a strong inhibitory effect on CML cells. Given that cell cycle arrest was not dependent on ROS induction, we speculate that this effect could be a direct consequence of NF-kappa B inhibition and if this mechanism was to be evaded, PTL and DMAPT induced cell death would be potentiated.
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