Temozolomide preferentially depletes cancer stem cells in glioblastoma.
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.
Beier
Dagmar
D
Department of Neurology, University of Regensburg, Medical School, Regensburg, Germany. Christoph.Beier@gmx.de
Röhrl
Stefanie
S
Pillai
Deepu R
DR
Schwarz
Stefanie
S
Kunz-Schughart
Leoni A
LA
Leukel
Petra
P
Proescholdt
Martin
M
Brawanski
Alexander
A
Bogdahn
Ulrich
U
Trampe-Kieslich
Ariane
A
Giebel
Bernd
B
Wischhusen
Jörg
J
Reifenberger
Guido
G
Hau
Peter
P
Beier
Christoph P
CP
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
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