Increased malignant behavior in neuroblastoma cells with acquired multi-drug resistance does not depend on P-gp expression.
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.
Kotchetkov
Rouslan
R
Interdisziplinäres Laboratorium für Tumor und Virus Forschung, Institut für Medizinische Virologie, Clinics of J-W. Goethe University, Frankfurt am Main, Germany.
Driever
Pablo Hernáiz
PH
Cinatl
Jaroslav
J
Michaelis
Martin
M
Karaskova
Jana
J
Blaheta
Roman
R
Squire
Jeremy A
JA
Von Deimling
Andreas
A
Moog
Jussi
J
Cinatl
Jindrich
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000378:metabolism / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D005720:Gamma Rays; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020128:Inhibitory Concentration 50; D007621:Karyotyping; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D020125:Mutation, Missense; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020112:Rhodamine 123 / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016895:Culture Media, Serum-Free; D016159:Tumor Suppressor Protein p53; D020112:Rhodamine 123; D014750:Vincristine; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt