Abstract
Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood. There are few effective strategies to manage therapy resistant GBM, and we lack diverse preclinical models of acquired TMZ resistance in which to test therapeutic strategies on TMZ resistant GBM. In this study, we create and characterize two new GBM cell lines resistant to TMZ in vitro, based on the 8MGBA and 42MGBA cell lines. Analysis of the TMZ resistant (TMZres) variants in conjunction with their parental, sensitive cell lines shows that acquisition of TMZ resistance is accompanied by broad phenotypic changes, including increased proliferation, migration, chromosomal aberrations, and secretion of cytosolic lipids. Importantly, each TMZ resistant model captures a different facet of the "go" (8MGBA-TMZres) or "grow" (42MGBA-TMZres) hypothesis of GBM behavior. These in vitro model systems will be important additions to the available tools for investigators seeking to define molecular mechanisms of acquired TMZ resistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Cytoskeleton / drug effects*
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Actin Cytoskeleton / metabolism
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Actin Cytoskeleton / ultrastructure
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Antineoplastic Agents, Alkylating / pharmacology*
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Apoptosis / drug effects
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Brain Neoplasms / drug therapy
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Carmustine / pharmacology
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects*
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Cell Size
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Chromosome Duplication
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DNA Modification Methylases / genetics
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DNA Modification Methylases / metabolism
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DNA Repair Enzymes / genetics
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DNA Repair Enzymes / metabolism
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic*
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Glioblastoma / drug therapy
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Humans
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Metabolic Networks and Pathways / drug effects
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Metabolic Networks and Pathways / genetics
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Metabolome / drug effects
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Models, Biological
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Temozolomide / pharmacology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Antineoplastic Agents, Alkylating
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Neoplasm Proteins
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Tumor Suppressor Proteins
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DNA Modification Methylases
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MGMT protein, human
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DNA Repair Enzymes
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Carmustine
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Temozolomide