Retinoic acid enhances sensitivity of neuroblastoma cells for imatinib mesylate.
BACKGROUND
Retinoids can induce differentiation of neuroblastoma (NB) cells and are in clinical use for the treatment of patients with NB. Despite improvements of standard treatment during the last years, many patients with NB still relapse and new treatment options for these patients are required.


METHODS
We analyzed NB cells after incubation with retinoids by using Affymetrix HG_U133A microarrays, reverse transcription-polymerase chain reaction (RT-PCR), and flow cytometry. Sequencing of RT-PCR products was applied for determination of CD117 mRNA sequences from NB cell lines. In addition, we tested sensitivity of NB cells for the kinase inhibitor imatinib mesylate after treatment with retinoids.


RESULTS
Treatment of NB cells with retinoids induced expression of several genes including the retinoid metabolizing enzymes CYP26A1 and CYP26B1. In addition, we observed up-regulation of CD117 (KIT), particularly after long-term treatment with retinoids. Sequencing of CD117 mRNA from NB cell lines revealed heterozygosity for a non-synonymous single nucleotide polymorphism in SH-SY5Y NB cells. Up-regulation of CD117 in NB cells correlated with increased sensitivity for the kinase inhibitor imatinib mesylate.


CONCLUSIONS
The combination of retinoids with kinase inhibitors might be worth exploring further for the treatment of NB patients.
Neumann
Ingo
I
Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Foell
Jürgen L
JL
Bremer
Marianne
M
Volkmer
Ines
I
Korholz
Dieter
D
Burdach
Stefan
S
Staege
Martin S
MS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D046228:Microarray Analysis; D009447:Neuroblastoma / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D000072516:Retinoic Acid 4-Hydroxylase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014212:Tretinoin; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; D000072516:Retinoic Acid 4-Hydroxylase; D019009:Proto-Oncogene Proteins c-kit