Different initial steps of apoptosis induced by two types of antineoplastic drugs.
O6-Methylguanine and O6-chloroethylguanine are primary DNA lesions produced by two types of antineoplastic drugs, 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, TMZ) and 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), respectively. They can be repaired by O6-methylguanine-DNA methyltransferase, coded by the Mgmt gene. Otherwise, these two types of lesions induce apoptosis in different ways. O6-Chloroethylguanine blocks DNA replication thereby inducing apoptosis. On the other hand, O6-methylguanine does not block DNA replication and the resulting O6-methylguanine-thymine mispair is recognized by mismatch repair-related proteins, including MLH1, thereby inducing apoptosis. Reflecting this, mouse cells lacking both MGMT and MLH1 are resistant to TMZ, but not to ACNU. The translocation of phosphatidylserine in cell membrane as well as a change of mitochondrial transmembrane potentials occurred in an MLH1-dependent manner after treatment with TMZ, but no such MLH1 dependency was observed in the case of ACNU treatment. By using cell lines defective in both APAF-1 and MGMT, it was revealed that the APAF-1 function is required for execution of apoptosis induced by either TMZ or ACNU. There is almost 12h delay in occurrence of apoptosis-related mitochondrial depolarization in TMZ-treated cells in comparison to those of ACNU-treated cells, reflecting the fact that at least one cycle of DNA replication is required to trigger apoptosis in the former case, but not in the latter.
Takagi
Yasumitsu
Y
Frontier Research Center, Fukuoka Dental College, 2-15-1, Tamura, Sawara-ku, Fukuoka, 814-0193, Japan. ytaka@college.fdcnet.ac.jp
Hidaka
Masumi
M
Sanada
Masayuki
M
Yoshida
Hiroki
H
Sekiguchi
Mutsuo
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D015376:Nimustine / Q000737:chemistry / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000502:physiology; D010718:Phosphatidylserines / Q000378:metabolism; D013329:Structure-Activity Relationship; D000077204:Temozolomide
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D010718:Phosphatidylserines; D015376:Nimustine; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1; D000077204:Temozolomide