Different modes of anthracycline interaction with topoisomerase II. Separate structures critical for DNA-cleavage, and for overcoming topoisomerase II-related drug resistance.
In contrast to the classic anthracyclines (doxorubicin and daunorubicin), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) mediated DNA-cleavage. This distinction may be important with respect to topo II-related drug resistance, and the aim of this study was to clarify drug-structures responsible for this difference. Various ACLA analogs were tested for: (a) interaction with purified topo II, (b) induction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxicity. A remarkable distinction was seen between analogs containing the chromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl group (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromophore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing analogs, including the aglycone RMN itself, effectively stimulated topo II-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited DNA cleavage and antagonized cytotoxicity mediated by RMN-containing drugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an altered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non-DNA cleaving AKV-containing compounds. Thus, our data show that one domain in the anthracycline is of particular importance for the interaction with topo II, namely the positions C-10 and C-11 in the chromophore, and further that at-MDR was circumvented by a COOCH3 substitution at position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.
Department of Oncology, Finsen Institute, Rigshospitalet, Blegdamsvej, Denmark.
P B
PB
Jensen
B S
BS
Sørensen
M
M
Sehested
E J
EJ
Demant
E
E
Kjeldsen
E
E
Friche
H H
HH
Hansen
D015250:Aclarubicin / Q000494:pharmacology; D000818:Animals; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009279:Naphthacenes / Q000494:pharmacology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D009279:Naphthacenes; D059005:Topoisomerase II Inhibitors; C049973:oxaunomycin; C027832:aklavinone; C015490:rhodomycinone; D015250:Aclarubicin; D004250:DNA Topoisomerases, Type II