Postreplicative mismatch repair plays a major role in mediating the cytotoxicity of agents generating O6-methylguanine in DNA. We previously showed that a methylating antitumor triazene compound, temozolomide, induces apoptosis and that the persistence of O6-methylguanine in DNA is required to trigger the process. We wanted to test whether the latter apoptotic signal is dependent on a functional mismatch repair system. To this end, we used two human lymphoblastoid cell lines (i.e., the mismatch repair-proficient TK6 line and its mismatch repair-deficient subline MT1) that are both deficient in O6-methylguanine repair. Temozolomide treatment of TK6 cells brought about efficient cell growth inhibition, G2/M arrest, and apoptosis, as indicated by the results of cytofluorimetric analysis of 5-bromo-2'-deoxyuridine incorporation and DNA content and evaluation of DNA fragmentation. The drug treatment resulted also in the induction of p53 and p21/waf-1 protein expression. In contrast, MT1 cells were highly resistant to the drug and no p53 and p21/waf-1 induction was observed. Importantly, we could show that MT1 cells are not deficient in the p53-dependent apoptosis pathway; treatment with etoposide, a topoisomerase II inhibitor, resulted in p53 and p21/waf-1 protein expression and apoptosis in both cell lines. In conclusion, we demonstrate the existence of a link between a functional mismatch repair system and the trigger of apoptosis in cells exposed to clinically relevant concentrations of temozolomide. The results also suggest that p53 induction in response to O6-guanine methylation involves the mismatch repair system.

D'Atri, S., Tentori, L., Lacal, P., Graziani, G., Pagani, E., Benincasa, E., et al. (1998). Involvement of the mismatch repair system in temozolomide-induced apoptosis. MOLECULAR PHARMACOLOGY, 54(2), 334-341.

Involvement of the mismatch repair system in temozolomide-induced apoptosis

TENTORI, LUCIO;GRAZIANI, GRAZIA;BONMASSAR, ENZO;
1998-08-01

Abstract

Postreplicative mismatch repair plays a major role in mediating the cytotoxicity of agents generating O6-methylguanine in DNA. We previously showed that a methylating antitumor triazene compound, temozolomide, induces apoptosis and that the persistence of O6-methylguanine in DNA is required to trigger the process. We wanted to test whether the latter apoptotic signal is dependent on a functional mismatch repair system. To this end, we used two human lymphoblastoid cell lines (i.e., the mismatch repair-proficient TK6 line and its mismatch repair-deficient subline MT1) that are both deficient in O6-methylguanine repair. Temozolomide treatment of TK6 cells brought about efficient cell growth inhibition, G2/M arrest, and apoptosis, as indicated by the results of cytofluorimetric analysis of 5-bromo-2'-deoxyuridine incorporation and DNA content and evaluation of DNA fragmentation. The drug treatment resulted also in the induction of p53 and p21/waf-1 protein expression. In contrast, MT1 cells were highly resistant to the drug and no p53 and p21/waf-1 induction was observed. Importantly, we could show that MT1 cells are not deficient in the p53-dependent apoptosis pathway; treatment with etoposide, a topoisomerase II inhibitor, resulted in p53 and p21/waf-1 protein expression and apoptosis in both cell lines. In conclusion, we demonstrate the existence of a link between a functional mismatch repair system and the trigger of apoptosis in cells exposed to clinically relevant concentrations of temozolomide. The results also suggest that p53 induction in response to O6-guanine methylation involves the mismatch repair system.
ago-1998
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
Tumor Suppressor Protein p53; DNA Repair; Apoptosis; Dacarbazine; Humans; Cyclin-Dependent Kinase Inhibitor p21; Nucleic Acid Heteroduplexes; Tumor Cells, Cultured; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Cell Cycle; Etoposide; Cell Division; Cyclins
D'Atri, S., Tentori, L., Lacal, P., Graziani, G., Pagani, E., Benincasa, E., et al. (1998). Involvement of the mismatch repair system in temozolomide-induced apoptosis. MOLECULAR PHARMACOLOGY, 54(2), 334-341.
D'Atri, S; Tentori, L; Lacal, P; Graziani, G; Pagani, E; Benincasa, E; Zambruno, G; Bonmassar, E; Jiricny, J
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/52925
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