Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species |
| |
| Authors: | Gabriela Flores‐Lopez Dafne Moreno‐Lorenzana Manuel Ayala‐Sanchez Socrates Aviles‐Vazquez Hector Torres‐Martinez Peter A Crooks Monica L Guzman Hector Mayani Antonieta Chávez‐González |
| |
| Affiliation: | 1. Leukemic Stem Cells Lab, Oncology Research Unit, Mexican Institute of Social Security, Oncology Hospital, “Siglo XXI” National Medical Center, Mexico City, Mexico;2. Hematology Department & BMT Unit, Medical Specialties Hospital, “La Raza” Medical Center, Mexican Institute of Social Security, Mexico City, Mexico;3. Department of Hip Surgery, Mexican Institute of Social Security, “Villa Coapa” General Hospital, Mexico City, Mexico;4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA;5. Division of Hematology/Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA;6. Hematopoietic Stem Cells Lab, Oncology Research Unit, Mexican Institute of Social Security, Oncology Hospital, “Siglo XXI” National Medical Center, Mexico City, Mexico |
| |
| Abstract: | 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‐κB activation. PTL and DMAPT inhibited cell proliferation and induced cell cycle arrest in G0 and G2 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. |
| |
| Keywords: |
CML
leukaemic stem cell parthenolide
ROS
|
|
|
