title: Temozolomide preferentially depletes cancer stem cells in glioblastoma.
abstract: The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients.
authors.affiliation: Department of Neurology, University of Regensburg, Medical School, Regensburg, Germany. Christoph.Beier@gmx.de
authors.forename: Dagmar
authors.initials: D
authors.lastname: Beier
authors.forename: Stefanie
authors.initials: S
authors.lastname: Röhrl
authors.forename: Deepu R
authors.initials: DR
authors.lastname: Pillai
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schwarz
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.forename: Petra
authors.initials: P
authors.lastname: Leukel
authors.forename: Martin
authors.initials: M
authors.lastname: Proescholdt
authors.forename: Alexander
authors.initials: A
authors.lastname: Brawanski
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bogdahn
authors.forename: Ariane
authors.initials: A
authors.lastname: Trampe-Kieslich
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Beier
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000096:biosynthesis; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002478:Cells, Cultured; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000494:pharmacology; D045643:DNA Repair Enzymes / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D010455:Peptides; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000494:pharmacology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide