RT Journal Article
SR Electronic
T1 Transcriptional Repression of <em>O</em><sup>6</sup>-Methylguanine DNA Methyltransferase Gene Rendering Cells Hypersensitive to <em>N,N</em>′-Bis(2-chloroethyl)-<em>N</em>-nitrosurea in Camptothecin-Resistant Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 517
OP 526
DO 10.1124/mol.107.043620
VO 74
IS 2
A1 Li-Chen Ma
A1 Ching-Chuan Kuo
A1 Jin-Fen Liu
A1 Li-Tzong Chen
A1 Jang-Yang Chang
YR 2008
UL http://molpharm.aspetjournals.org/content/74/2/517.abstract
AB O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl-adducts from the O6-guanine in DNA and is a crucial defense against O6-alkylating agent-induced cytotoxicity. We demonstrated here that two camptothecin (CPT)-resistant cell lines (CPT30 and KB100) were more sensitive to N,N′-bis(2-chloroethyl)-N-nitrosurea (BCNU) than their parental cells. Enhanced sensitivity to BCNU in these two CPT-resistant cells involved transcriptional repression of the MGMT gene. The mechanism of MGMT gene down-regulation in CPT-resistant cells was not through gene abnormality, mRNA stability, and CpG island hypermethylation. However, the high level of methyl-CpG-binding protein 2 (MeCP2) and dimethylation of H3K9 in the promoter region were found in CPT30 and KB100 cells. Furthermore, increased MeCP2 binding on MGMT promoter was also found to be correlated with MGMT gene-silencing in short-term CPT treatment; thus, enhanced BCNU sensitivity was found in CPT-treated cells. Taken together, we suggest that CPT is able to suppress the transcription of the MGMT gene through recruiting of MeCP2 and H3K9 dimethylation, thus causing a synergistic interaction with BCNU. These findings provide a possible explanation regarding why the combination of CPT and BCNU results in a better objective response than single-use alone. In addition, this study supports a new indication for treating patients who are receiving refractory CPT derivatives with BCNU. The American Society for Pharmacology and Experimental Therapeutics