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Molekulare Enzymologie und Wirkstofftargets

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Extracts of Seven Indian Plants Inhibit Human Topoisomerase I and Partially Inhibit Human Topoisomerase II

Indrani Kar,Hemanta K. Majumder and Rajagopal Chattopadhyaya

Objective: We are trying to rationalize the known antioxidant and anticancer activities of the extracts of some of these plants through their inhibition of human topoisomerases I and II, as it is crucial to develop novel nontoxic topoisomerase inhibitors that can spare normal cells.

Methods: Standard topoisomerase I and II assays with and without the plant extracts and associated analyses.

Results: Extracts of Acacia catechu, Emblica officinalis, Terminalia belerica, Terminalia chebula, Spondias dulcis, completely inhibit human topoisomerase I at 40 μg/mL concentration while Hemidesmus indicus and Dolichos biflorus extracts inhibit partially at the same concentration when included in standard assays. Extracts of the same five plants which inhibit human topoisomerase I strongly are known to possess anticancer activity, while the other two are antioxidant only. Spinacia oleracea extract does not significantly inhibit human topoisomerase I and serves as a negative control. Extracts of Acacia catechu, Terminalia chebula and Spondias dulcis show 20–80% inhibition of human topoisomerase I at even 9 μg/mL concentration. All seven plant extracts partially inhibit human topoisomerase II at 120 μg/mL concentration in the decatenation assay. Chebulagic and chebulinic acids purified from Terminalia chebula extract inhibited human topoisomerase I at around 2 μM and 3 μM respectively. Preincubation dilution assays performed with the plant extracts and the two acids purified from Terminalia chebula show the inhibition of human topoisomerase I at even lower concentrations, implying the inhibitor molecules bind the enzyme very tightly due to the preincubations.

Conclusions: The nuclear fragmentation leading to apoptosis observed earlier in cancerous cell lines in the presence of such plant extracts may thus be explained by the inhibition of topoisomerases in addition to modulation of modulation of Fenton reaction-mediated damage to DNA constituents shown elsewhere.