RRC ID 42358
Author Sato K, Kitajima Y, Kohya N, Miyoshi A, Koga Y, Miyazaki K.
Title Deficient MGMT and proficient hMLH1 expression renders gallbladder carcinoma cells sensitive to alkylating agents through G2-M cell cycle arrest.
Journal Int J Oncol
Abstract The aim of this study was to assess whether combined evaluation of O6-methylguanine methyltransferase (MGMT) and hMLH1 status determines sensitivity to monofuntional alkylating agents such as N-methyl-N-nitrosourea (MNU) and dacarbazine (DTIC) against gallbladder carcinoma cells. The molecular mechanism behind MGMT and hMLH1 status affecting the cell cycle was also addressed. Using 5 gallbladder cancer carcinoma lines and 1 colon carcinoma cell line (SW48), MGMT and hMLH1 expression was analyzed using RT-PCR and Western blotting. MGMT and hMLH1 status in the 6 cell lines was compared with drug sensitivity to MNU. As a result, cell lines that were MGMT-/hMLH1+ had the highest sensitivity to MNU, compared with MGMT+/hMLH1+ and MGMT-/hMLH1- cells. In flow cytometric analysis, G2-M cell cycle arrest was specifically observed in GB-d1 cells with MGMT-/hMLH1+ and expression of cyclin A and Cdc2 in GB-d1 cells was significantly reduced by MNU treatment, but not observed in KMG-C cells with MGMT+/hMLH1+. Finally, we assessed the in vitro and in vivo effect of the clinically used alkylating agent DTIC in these cells. The highest sensitivity to DTIC was also observed in MGMT-/hMLH1+. In conclusion, MNU suppressed cell proliferation of MGMT-/hMLH1+ gallbladder carcinoma cells by arresting the cell cycle at the G2-M phase, accompanied by down-regulation of cyclin A and Cdc2. These results indicated that expression of MGMT and hMLH1 could be used to select candidates for alkylating agent chemotherapy against gallbladder carcinoma.
Volume 26(6)
Pages 1653-61
Published 2005-6-1
PMID 15870882
MeSH Adaptor Proteins, Signal Transducing Animals Antineoplastic Agents, Alkylating / pharmacology* Carrier Proteins Cell Division / drug effects* Cell Line, Tumor Dacarbazine / pharmacology Dacarbazine / therapeutic use Female Flow Cytometry G2 Phase / drug effects* Gallbladder Neoplasms / chemistry Gallbladder Neoplasms / drug therapy* Gallbladder Neoplasms / pathology Humans Methylnitrosourea / pharmacology Mice Mice, Inbred BALB C MutL Protein Homolog 1 Neoplasm Proteins / analysis* Neoplasm Proteins / genetics Neoplasms, Experimental / drug therapy Nuclear Proteins / analysis* Nuclear Proteins / genetics O(6)-Methylguanine-DNA Methyltransferase / analysis* O(6)-Methylguanine-DNA Methyltransferase / genetics RNA, Messenger / analysis
IF 3.899
Times Cited 7
Human and Animal Cells TGBC2TKB(RCB1130)