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Biomed Res Int. 2015;2015:673512. doi: 10.1155/2015/673512. Epub 2015 Nov 4.

Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib.

Author information

1
Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
2
Department of Flow Cytometry, Medical Center for Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland.
3
Department of Infectious and Liver Diseases, Medical University of Lodz, Kniaziewicza 1/5, 92-347 Lodz, Poland.
4
Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland.
5
Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA.

Abstract

Imatinib resistance is an emerging problem in the therapy of chronic myeloid leukemia (CML). Because imatinib induces apoptosis, which may be coupled with mitochondria and DNA damage is a prototype apoptosis-inducing factor, we hypothesized that imatinib-sensitive and -resistant CML cells might differentially express apoptosis-related mitochondrially encoded genes in response to genotoxic stress. We investigated the effect of doxorubicin (DOX), a DNA-damaging anticancer drug, on apoptosis and the expression of the mitochondrial NADH dehydrogenase 3 (MT-ND3) and cytochrome b (MT-CYB) in model CML cells showing imatinib resistance caused by Y253H mutation in the BCR-ABL1 gene (253) or culturing imatinib-sensitive (S) cells in increasing concentrations of imatinib (AR). The imatinib-resistant 253 cells displayed higher sensitivity to apoptosis induced by 1 μM DOX and this was confirmed by an increased activity of executioner caspases 3 and 7 in those cells. Native mitochondrial potential was lower in imatinib-resistant cells than in their sensitive counterparts and DOX lowered it. MT-CYB mRNA expression in 253 cells was lower than that in S cells and 0.1 μM DOX kept this relationship. In conclusion, imatinib resistance may be associated with altered mitochondrial response to genotoxic stress, which may be further exploited in CML therapy in patients with imatinib resistance.

PMID:
26618175
PMCID:
PMC4649080
DOI:
10.1155/2015/673512
[Indexed for MEDLINE]
Free PMC Article

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