Open AccessParthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species
Author(s) -
FloresLopez Gabriela,
MorenoLorenzana Dafne,
AyalaSanchez Manuel,
AvilesVazquez Socrates,
TorresMartinez Hector,
Crooks Peter A.,
Guzman Monica L.,
Mayani Hector,
ChávezGonzález Antonieta
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13755
Subject(s) - parthenolide , cell cycle , chemistry , programmed cell death , cell cycle checkpoint , myeloid , population , reactive oxygen species , myeloid leukemia , haematopoiesis , cancer research , microbiology and biotechnology , cell , biology , apoptosis , stem cell , biochemistry , medicine , environmental health
Abstract Tyrosine kinase inhibitors ( TKI ) have become a first‐line treatment for chronic myeloid leuakemia ( CML ). TKI s 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 LSC s in acute myeloid leukaemia ( AML ), on CML bulk and CML primitive ( CD 34 + 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 ‐κB 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 ‐κB inhibition and if this mechanism was to be evaded, PTL and DMAPT induced cell death would be potentiated.