Imatinib resistance in multidrug-resistant K562 human leukemic cells

Leuk Res. 2009 May;33(5):710-6. doi: 10.1016/j.leukres.2008.09.024. Epub 2008 Nov 1.

Abstract

The multidrug resistance phenotype (MDR) is one of the major causes of failure in cancer chemotherapy and it is associated with the over-expression of P-glycoprotein (P-gp or MDR1) in tumor cell membranes. A constitutive NF-kappaB activity has been observed in several haematological malignancies and this is associated with its anti-apoptotic role. In the present work, the relationship between NF-kappaB and MDR phenotype was evaluated in wild type K562 human leukemic cells (K562-WT) and in its vincristine-resistant counterpart, K562-Vinc cells. These data showed that K562-Vinc cells, which express an active P-gp, exhibited MDR phenotype. The resistant indexes (IC(50)(K562-Vinc)/IC(50)(K562-WT)) for structurally unrelated drugs like imatinib, doxorubicin and colchicine were 8.0+/-0.3, 2.8+/-0.4 and 44.8+/-8.8, respectively. The imatinib resistance was reversed by P-gp blockade suggesting the involvement of P-gp in imatinib transport. We observed that NF-kappaB was constitutively activated in both cell lines but in a lesser extent in K562-Vinc. The inhibition of NF-kappaB with BAY 11-7082 increased the cytotoxicity of imatinib in K562-Vinc cells but not in K562-WT. Further, the co-administration of imatinib and BAY 11-7082 sensitized multidrug-resistant K562 cells to cell death as detected by increased percentage of annexin V positive cells. The induced cell death in K562-Vinc cells was associated with activation of caspases 9 and 3. Finally, we provide data showing that BAY 11-7082 down-regulates the expression of P-gp suggesting that the activity of NF-kappaB could be functionally associated to this protein in K562 cells. Our results indicate that the vincristine-resistant K562 cells which developed MDR phenotype, exhibited resistance to imatinib associated with a functional P-gp over-expression. This resistance could be partially overcome by the inhibition of NF-kappaB pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Base Sequence
  • Benzamides
  • Blotting, Western
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Electrophoretic Mobility Shift Assay
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • NF-kappa B / metabolism
  • Nitriles / pharmacology
  • Oligodeoxyribonucleotides
  • Piperazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Sulfones / pharmacology

Substances

  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Benzamides
  • NF-kappa B
  • Nitriles
  • Oligodeoxyribonucleotides
  • Piperazines
  • Pyrimidines
  • Sulfones
  • Imatinib Mesylate