title: Doxorubicin Differentially Induces Apoptosis, Expression of Mitochondrial Apoptosis-Related Genes, and Mitochondrial Potential in BCR-ABL1-Expressing Cells Sensitive and Resistant to Imatinib.
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.
authors.affiliation: Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Synowiec
authors.affiliation: Department of Flow Cytometry, Medical Center for Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Hoser
authors.affiliation: Department of Infectious and Liver Diseases, Medical University of Lodz, Kniaziewicza 1/5, 92-347 Lodz, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Bialkowska-Warzecha
authors.affiliation: Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Pawlowska
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
authors.affiliation: Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Blasiak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D050259:Genes, Mitochondrial / Q000187:drug effects* / Q000235:genetics; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D012333:RNA, Messenger; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl