RT Journal Article
SR Electronic
T1 Involvement of the Mismatch Repair System in Temozolomide-Induced Apoptosis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 334
OP 341
DO 10.1124/mol.54.2.334
VO 54
IS 2
A1 Stefania D’Atri
A1 Lucio Tentori
A1 Pedro Miguel Lacal
A1 Grazia Graziani
A1 Elena Pagani
A1 Elena Benincasa
A1 Giovanna Zambruno
A1 Enzo Bonmassar
A1 Josef Jiricny
YR 1998
UL http://molpharm.aspetjournals.org/content/54/2/334.abstract
AB Postreplicative mismatch repair plays a major role in mediating the cytotoxicity of agents generatingO 6-methylguanine in DNA. We previously showed that a methylating antitumor triazene compound, temozolomide, induces apoptosis and that the persistence ofO 6-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 inO 6-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 toO 6-guanine methylation involves the mismatch repair system.