bis(2,6-dioxopiperaxine) derivatives, topoisomerase II inhibitors which do not form a DNA cleavable complex, induce thymocyte apoptosis.
Internucleosomal DNA fragmentation and cell death were induced dose- and time-dependently by incubation of mouse thymocytes with bis(2,6-dioxopiperazine) derivatives, ICRF-154 and MST-16, inhibitors of topoisomerase II, which do not induce cleavable complex formation. The process was inhibited by actinomycin D and cycloheximide, indicating that the process was an active apoptotic process. Bis(2,6-dioxopiperazine) derivatives have been known to inhibit the etoposide-induced DNA cleavage, but ICRF-154 did not inhibit etoposide-induced apoptosis in thymocytes at 6 h incubation, suggesting that DNA cleavage is not essential for induction of apoptosis by topoisomerase II inhibitors. The alteration of DNA helicity induced by a subtle inhibition of topoisomerase II activity may have an important role in the induction of apoptosis in thymocytes, since topoisomerase II is a major component of the nuclear matrix that can regulate gene expression.
Onishi
Y
Y
Department of Biochemistry, Tokyo Dental College, Chiba, Japan.
Azuma
Y
Y
Kizaki
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009690:Nucleic Acid Conformation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011929:Razoxane / Q000031:analogs & derivatives* / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D010879:Piperazines; D059004:Topoisomerase I Inhibitors; D003609:Dactinomycin; D011929:Razoxane; D005047:Etoposide; D003513:Cycloheximide; C000283:1,2-bis(3,5-dioxopiperazin-1-yl)ethane; C057773:sobuzoxane