Mechanism of action of the antileukemic xanthone psorospermin: DNA strand breaks, abasic sites, and protein-DNA cross-links.
Psorospermin, a cytotoxic dihydrofuranoxanthone isolated from Psorospermum febrifugum, produced aberrant simian virus 40 DNA replication intermediates when added to lytically infected CV-1 monkey kidney cells. The aberrant viral intermediates showed dose-dependent DNA strand breaks and protein-DNA cross-links, as well as decreased electrophoretic mobility. Simian virus 40 DNA from psorospermin-treated cells was shown to contain numerous abasic (apyrimidinic/apurinic) sites. The density of abasic sites was a function of the psorospermin dose. We conclude that psorospermin causes extensive loss of DNA bases in vivo. Primary amine groups of cellular proteins are known to react with abasic sites to form covalent protein-DNA cross-links and DNA strand breaks. Cytochrome c cross-linked spontaneously to viral DNA prepared from psorospermin-treated cells but not to DNA from untreated cells. This suggests that the protein-DNA cross-links and many of the DNA strand breaks observed in vivo result from reactions between abasic sites and chromosomal proteins. It is likely that the protein-DNA cross-links and DNA strand breaks contribute to the cytotoxicity and antineoplastic activity of psorospermin.
Permana
P A
PA
Department of Radiology, Ohio State University, Columbus 43210.
Ho
D K
DK
Cassady
J M
JM
Snapka
R M
RM
D000447:Aldehydes / Q000378:metabolism; D000588:Amines / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D012545:Schiff Bases / Q000378:metabolism; D013539:Simian virus 40 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014966:Xanthenes / Q000633:toxicity*; D044004:Xanthones
D000447:Aldehydes; D000588:Amines; D000972:Antineoplastic Agents, Phytogenic; D004279:DNA, Viral; D012545:Schiff Bases; D014966:Xanthenes; D044004:Xanthones; C025543:psorospermin; D003577:Cytochrome P-450 Enzyme System; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II