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 antit umor activities and was demonstrated to stabilize the DNA topoisomerase II (Topo II) cleavage complex in vitro and in vivo. In the present work we inv estigated the possible mechanism through which disturbance of Topo II by sa lvicine led to cell death. We found that salvicine induced DNA strand break s in human promyelocytic leukemia HL-60 cells and DNA damage correlated wit h 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 ' regio n 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, whi ch could lead to growth inhibition mediated by alterations of the expressio n of selected proliferation regulatory genes, such as c-myc, c-fos and c-ju n, and ultimately cell death. (C) 2001 Published by Elsevier Science B.V. o n behalf of the Federation of European Biochemical Societies.