Relationship between topoisomerase II-DNA cleavable complexes, apoptosis and cytotoxic activity of anthracyclines in human cervix carcinoma cells.
The use of anthracyclines as antitumor drugs dates back to the 1970s, but the mechanism of the cytotoxicity of these compounds has long been a matter of debate. There is increasing evidence indicating that drug-induced cytotoxicity commonly converges on the induction of apoptosis. Many authors point to the fact that double-strand breaks, resulting from stabilization of cleavable complexes, are the signal for the initiation of the apoptotic cascade. In this work, the possible correlation between stabilization of topoisomerase II (topoII)-DNA complexes, apoptosis induction and cytotoxicity was studied. Parental human cervix carcinoma cells, HeLa, and its subline resistant to vinblastine, KB-V1, were exposed to doxorubicin (DOX) and the novel anthracyclines annamycin and WP903, given at the concentrations 0.2 and 2.0 microg/ml (DOX and annamycin) or 0.2 and 1.0 microg/ml (WP903). It was found that annamycin was the strongest topoII poison in HeLa cells at both concentrations used, whereas poly (ADP-ribose) polymerase (PARP) cleavage was observed dose-dependently in KB-V1 cells treated with annamycin or WP903. Simultaneously, apoptosis, observed as cell morphology or phosphatidylserine translocation, was evident in both cell types exposed to the novel anthracyclines, independent of concentration. DOX appeared to be the weakest apoptotic inducer. On the basis of these studies, it can be suggested that topoII poisoning is not the key process leading to apoptosis and seems to be cell specific. PARP cleavage is probably not an evident marker of anthracycline-induced apoptosis which, in turn, does not seem to be the determinant in the cytotoxic action of these compounds. The efficiency of anthracycline antibiotics, interpreted as cytotoxic action, was dependent on cell type.
Gruber
Beata M
BM
National Institute of Public Health, Department of Biochemistry and Biopharmaceuticals, Chelmska 30/34 Str., 00-725 Warsaw, Poland. b-gruber@il.waw.pl
Anuszewska
Elzbieta L
EL
Bubko
Irena
I
Gozdzik
Aneta
A
Priebe
Waldemar
W
Fokt
Izabela
I
D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D059005:Topoisomerase II Inhibitors; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D004250:DNA Topoisomerases, Type II; C080315:annamycin