Induction of bulk and c-myc P2 promoter-specific DNA damage by an anti-topoisomerase II agent salvicine is an early event leading to apoptosis in HL-60 cells.
Salvicine is a novel diterpenoid quinone derivative possessing strong antitumor activities and was demonstrated to stabilize the DNA topoisomerase II (Topo II) cleavage complex in vitro and in vivo. In the present work we investigated the possible mechanism through which disturbance of Topo II by salvicine led to cell death. We found that salvicine induced DNA strand breaks in human promyelocytic leukemia HL-60 cells and DNA damage correlated with cell growth inhibition. DNA damage induced by brief exposure to salvicine could be partially reversed, but early DNA breaks triggered the process of apoptosis. Preferential damage in the P2 promoter region of the oncogene c-myc was detected, whereas no obvious DNA damage was found in the 3' region of the same gene. Furthermore, the expression of some protooncogenes such as c-myc, c-fos and c-jun was examined, showing that salvicine produced a reduction in the transcription rate of c-myc in a dose-dependent manner and a marked induction of c-fos and c-jun expression was observed. It appears possible that DNA damage within such genomic regions is an early event, which could lead to growth inhibition mediated by alterations of the expression of selected proliferation regulatory genes, such as c-myc, c-fos and c-jun, and ultimately cell death.
Meng
L
L
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, PR China.
Ding
J
J
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D016259:Genes, myc / Q000235:genetics*; D018922:HL-60 Cells; D006801:Humans; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D012333:RNA, Messenger; D059005:Topoisomerase II Inhibitors; C122096:salvicine; D004250:DNA Topoisomerases, Type II