Abstract | OBJECT: METHODS: The effects of TMZ alone (100 microg) and after exposure to BG (50 microg) were assessed in two glioblastoma cell lines, U373-MG and T98G, respectively, sensitive and resistant to TMZ. Cell viability was assessed using trypan blue; cell cycle analysis by fluorescence-activated cell sorter; and apoptosis and autophagy by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and acridine orange staining, respectively. Furthermore, the involvement of an autophagy marker, microtubule-associated light chain 3 (LC3), was assessed. Temozolomide suppressed the growth of and caused cell cycle arrest in the G2-M phase of U373-MG cells but not T98G cells. Exposure to BG prior to TMZ resulted in a significant decrease in cell viability as well as cell cycle arrest in the G2-M phase in T98G cells (p < 0.05). Although apoptosis was not detected on TUNEL staining, programmed cell death Type II (autophagy) was detected after exposure to BG and TMZ in T98G cells. CONCLUSIONS: These results indicate that inhibition of AGT by BG can render previously resistant glioma cells sensitive to TMZ treatment. The mechanism of cell demise following BG-TMZ treatment seems to be autophagy and not apoptosis. Combination therapy involving TMZ and an AGT inhibitor may be an effective strategy to treat resistant gliomas.
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Authors | Takao Kanzawa, Joshua Bedwell, Yasuko Kondo, Seiji Kondo, Isabelle M Germano |
Journal | Journal of neurosurgery
(J Neurosurg)
Vol. 99
Issue 6
Pg. 1047-52
(Dec 2003)
ISSN: 0022-3085 [Print] United States |
PMID | 14705733
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents, Alkylating
- Enzyme Inhibitors
- O(6)-benzylguanine
- Guanine
- Dacarbazine
- O(6)-Methylguanine-DNA Methyltransferase
- Temozolomide
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Topics |
- Antineoplastic Agents, Alkylating
(therapeutic use)
- Apoptosis
(genetics)
- Cell Line, Tumor
- Cell Survival
(genetics)
- DNA Repair
(drug effects)
- Dacarbazine
(analogs & derivatives, therapeutic use)
- Drug Resistance, Neoplasm
(drug effects)
- Enzyme Inhibitors
(pharmacology)
- Glioma
(drug therapy, genetics)
- Guanine
(analogs & derivatives, pharmacology)
- Humans
- O(6)-Methylguanine-DNA Methyltransferase
(antagonists & inhibitors)
- Temozolomide
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