Publication: Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression.
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Identifiers
Date
2015-10-08
Authors
Perazzoli, Gloria
Prados, Jose
Ortiz, Raul
Caba, Octavio
Cabeza, Laura
Berdasco, Maria
Gónzalez, Beatriz
Melguizo, Consolación
Advisors
Journal Title
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Publisher
Public Library of Science
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Abstract
BACKGROUND
The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated.
METHODS
Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed.
RESULTS
Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines.
CONCLUSIONS
These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.
Description
Journal Article; Research Support, Non-U.S. Gov't;
MeSH Terms
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents::Antineoplastic Agents, Alkylating
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Aza Compounds::Azacitidine
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::DNA Restriction-Modification Enzymes::DNA Modification Methylases
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::DNA Repair Enzymes
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Triazenes::Dacarbazine
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic
Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma
Medical Subject Headings::Chemicals and Drugs::Carbohydrates::Glycoconjugates::Glycoproteins
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines::Purinones::Hypoxanthines::Guanine
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::ATP-Binding Cassette Transporters::P-Glycoproteins
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Tumor Suppressor Proteins
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Antigens, Differentiation::Antigens, CD
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base Sequence::Regulatory Sequences, Nucleic Acid::Promoter Regions, Genetic
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Aza Compounds::Azacitidine
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::DNA Restriction-Modification Enzymes::DNA Modification Methylases
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::DNA Repair Enzymes
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Triazenes::Dacarbazine
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic
Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma
Medical Subject Headings::Chemicals and Drugs::Carbohydrates::Glycoconjugates::Glycoproteins
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines::Purinones::Hypoxanthines::Guanine
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::ATP-Binding Cassette Transporters::P-Glycoproteins
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Tumor Suppressor Proteins
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Biological Markers::Antigens, Differentiation::Antigens, CD
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Base Sequence::Regulatory Sequences, Nucleic Acid::Promoter Regions, Genetic
DeCS Terms
CIE Terms
Keywords
Antineoplásicos alquilantes, Azacitidina, Línea celular tumoral, Metilación de ADN, Metilasas de modificación del ADN, Enzimas reparadoras del ADN, Tumor Suppressor Proteins, Dacarbazina, Resistencia a antineoplásicos, Epigénesis genética, Expresión génica, Regulación neoplásica de la expresión génica, Glicoproteínas, Guanina, Concentración 50 inhibidora, Glicoproteína P, Péptidos, Regiones promotoras genéticas, Proteínas supresoras de tumor, Antígenos CD, Regiones promotoras genéticas
Citation
Perazzoli G, Prados J, Ortiz R, Caba O, Cabeza L, Berdasco M, et al. Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression. PLoS ONE. 2015; 10(10):e0140131