1. Mitochondrial mutagenesis in BCR-ABL1-expressing cells sensitive and resistant to imatinib
- Author
-
Tomasz Skorski, Jolanta Białkowska-Warzecha, Janusz Blasiak, Grazyna Hoser, and Elzbieta Pawlowska
- Subjects
0301 basic medicine ,DNA Copy Number Variations ,DNA damage ,DNA repair ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,DNA, Mitochondrial ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,03 medical and health sciences ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,neoplasms ,Chemistry ,Mutagenesis ,Imatinib ,Transfection ,030104 developmental biology ,Imatinib mesylate ,Drug Resistance, Neoplasm ,Cell culture ,Imatinib Mesylate ,Cancer research ,Drug Screening Assays, Antitumor ,Tyrosine kinase ,DNA Damage ,medicine.drug - Abstract
Imatinib revolutionized the treatment of chronic myeloid leukemia (CML) with the expression of the BCR-ABL1 tyrosine kinase, but imatinib resistance is an emerging problem. Imatinib can hinder the inhibitory effects of BCR-ABL1 on mitochondrial apoptotic pathway, so mitochondrial mutagenesis can be important for its action. To explore the mechanisms of imatinib resistance we created a mouse-derived CML model cells consisting of parental 32D cells (P) and cells transfected with the BCR-ABL1 gene (S cells) or its variants with the Y253H or T315I mutations (253 and 315 cells, respectively), conferring resistance to imatinib. A fraction of the S cells was cultured in increasing concentrations of imatinib, acquiring resistance to this drug (AR cells). The 253, 315 and AR cells, in contrast to S cells, displayed resistance to imatinib. We observed that the T315I cells displayed greater extent of H2O2-induced mtDNA damage than their imatinib-sensitive counterparts. No difference in the sensitivity to UV radiation was observed among all the cell lines. A decrease in the extent of H2O2-induced mtDNA damage was observed during a 120-min repair incubation in all cell lines, but it was significant only in imatinib-sensitive and T315I cells. No difference in the copy number of mtDNA and frequency of the 3,867-bp deletion was observed and genotoxic stress induced by H2O2 or UV did not change this relationship. In conclusion, some aspects of mtDNA mutagenesis, including sensitivity to oxidative stress and DNA repair can contribute to imatinib resistance in BCR-ABL1-expressing cells.
- Published
- 2016
- Full Text
- View/download PDF