Increased malignant behavior in neuroblastoma cells with acquired multi-drug resistance does not depend on P-gp expression

Int J Oncol. 2005 Oct;27(4):1029-37.


Acquisition of P-gp-mediated multidrug-resistance does not always correlate with observed malignant behavior of NB. To characterize alterations accompanying development of multidrug-resistance in NB we established two neuroblastoma cell sublines resistant to vincristine (UKF-NB-3rVCR10) and doxorubicin (UKF-NB-3rDOX20). UKF-NB-3rVCR10 and UKF-NB-3rDOX20 overexpressed functional P-gp and developed an increased malignant phenotype: presented constitutive phosphorylation of AKT, resistance to gamma-irradiation, and had increased survival in serum-free medium. Inhibition of P-gp restored chemosensitivity but did not affect increased survival in serum-free medium and sensitivity to gamma-irradiation. Inhibition of AKT had no influence on chemoresistance but restored sensitivity to serum starvation. Both resistant cell lines acquired additional chromosomal changes. UKF-NB-3rVCR10 cells acquired a missense P53 mutation in exon 5, an increased MYCN amplification, an enhanced adhesion to endothelium, a decreased NCAM expression, a distinctly higher clonogenicity, and an increased in vivo tumorigenicity. We conclude that acquisition of increased malignant behavior in neuroblastoma occurs concomitantly with multidrug-resistance and is P-gp-independent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Blotting, Western
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Separation
  • Cell Survival
  • Cells, Cultured
  • Culture Media, Serum-Free / metabolism
  • Culture Media, Serum-Free / pharmacology
  • DNA Mutational Analysis
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Doxorubicin / pharmacology
  • Drug Resistance
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Exons
  • Female
  • Flow Cytometry
  • Gamma Rays
  • Genes, p53 / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Inhibitory Concentration 50
  • Karyotyping
  • Mice
  • Mice, Nude
  • Mutation
  • Mutation, Missense
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology*
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rhodamine 123 / pharmacology
  • Time Factors
  • Tumor Suppressor Protein p53 / metabolism
  • Vincristine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Culture Media, Serum-Free
  • Tumor Suppressor Protein p53
  • Rhodamine 123
  • Vincristine
  • Doxorubicin
  • Proto-Oncogene Proteins c-akt