Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line
- 1 September 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 5 (9), 2182-2192
- https://doi.org/10.1158/1535-7163.mct-05-0428
Abstract
Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair–deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor. [Mol Cancer Ther 2006;5(9):2182–92]Keywords
This publication has 47 references indexed in Scilit:
- Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte developmentDevelopmental Biology, 2006
- Identification of genes differentially expressed in glioblastoma versus pilocytic astrocytoma using Suppression Subtractive HybridizationOncogene, 2005
- Akt Activation Suppresses Chk2-Mediated, Methylating Agent–Induced G2 Arrest and Protects from Temozolomide-Induced Mitotic Catastrophe and Cellular SenescenceCancer Research, 2005
- The genome sequence of the rice blast fungus Magnaporthe griseaNature, 2005
- LIF receptor signaling modulates neural stem cell renewalMolecular and Cellular Neuroscience, 2004
- Tumor‐specific exon creation of the HELLS/SMARCA6 gene in non‐small cell lung cancerInternational Journal of Cancer, 2004
- Suppression of growth and tumorigenicity in the prostate tumor cell line M12 by overexpression of the transcription factor SOX9Oncogene, 2004
- NF-κB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cellsCell Death & Differentiation, 2003
- Overexpression of the MEN/ELL Protein, an RNA Polymerase II Elongation Factor, Results in Transformation of Rat1 Cells with Dependence on the Lysine-rich RegionPublished by Elsevier BV ,1998
- Confluence‐dependent resistance in human colon cancer cells: Role of reduced drug accumulation and low intrinsic chemosensitivity of resting cellsInternational Journal of Cancer, 1992