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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics*
  • Cell Line
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Expression / drug effects*
  • Gene Expression / genetics
  • Genes, Mitochondrial / drug effects*
  • Genes, Mitochondrial / genetics
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • RNA, Messenger / genetics

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • RNA, Messenger
  • Doxorubicin
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl