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Topoisomerase poisoning activity of novel disaccharide anthracyclines
F Guano1, P Pourquier, S Tinelli
1Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Abstract:
Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases IIalpha and IIbeta. Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases IIalpha and IIbeta. The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I.
Insights
Novel disaccharide analogs and idarubicin are potent poisons of topoisomerases IIalpha and IIbeta. Their cytotoxic activity depends on topoisomerase II content, with some dependence on topoisomerase I.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Doxorubicin and idarubicin are effective anticancer drugs targeting human hematological malignancies and solid tumors.
- These anthracyclines are known topoisomerase II poisons, but some analogs also affect topoisomerase I.
- Understanding topoisomerase poisoning mechanisms is crucial for developing new anticancer agents.
Purpose of the Study:
- To evaluate novel disaccharide analogs and idarubicin for their topoisomerase I and II (IIalpha and IIbeta) poisoning effects.
- To investigate the structure-activity relationship of these compounds regarding enzyme poisoning and cytotoxicity.
- To assess the in vitro and in vivo activity of these agents.
Main Methods:
- In vitro DNA cleavage assays to determine topoisomerase poisoning.
- Yeast-based systems to evaluate in vivo enzyme poisoning and cytotoxicity.
- Assays included novel disaccharide analogs and the parent drug, idarubicin.
Main Results:
- The novel disaccharide analogs and idarubicin potently poisoned both topoisomerase IIalpha and IIbeta.
- An axial orientation of the second sugar in the analogs was essential for poisoning activity and cytotoxicity.
- Compounds stimulated topoisomerase I-mediated DNA cleavage at low concentrations in vitro and showed weak dependence on cellular topoisomerase I for yeast cell killing.
Conclusions:
- The study elucidates the molecular mechanisms of topoisomerase poisoning by novel anthracycline analogs.
- Structural determinants for anthracycline activity against topoisomerase I and II have been identified.
- Findings may aid in the rational design of new anticancer drugs targeting topoisomerases.