Abstract
DNA replication inhibitors are utilized extensively in studies of molecular biology and as chemotherapy agents in clinical settings. The inhibition of DNA replication often triggers double-stranded DNA breaks (DSBs) at stalled DNA replication sites, resulting in cytotoxicity. In East Asia, some traditional medicines are administered as anticancer drugs, although the mechanisms underlying their pharmacological effects are not entirely understood. In this study, we screened Japanese herbal medicines and identified two benzylisoquinoline alkaloids (BIAs), berberine and coptisine. These alkaloids mildly induced DSBs, and this effect was dependent on the function of topoisomerase I (Topo I) and MUS81-EME1 structure-specific endonuclease. Biochemical analysis revealed that the action of BIAs involves inhibiting the catalytic activity of Topo I rather than inducing the accumulation of the Topo I-DNA complex, which is different from the action of camptothecin (CPT). Furthermore, the results showed that BIAs can act as inhibitors of Topo I, even against CPT-resistant mutants, and that the action of these BIAs was independent of CPT. These results suggest that using a combination of BIAs and CPT might increase their efficiency in eliminating cancer cells.
Highlights
DNA replication inhibitors are utilized extensively in studies of molecular biology and as chemotherapy agents in clinical settings
The analysis of available data for natural compounds revealed that berberine and palmatine are major components of these herbal medicines, and we subsequently identified berberine and coptisine
We found that the DNA-binding affinities of berberine, coptisine, and palmatine were similar (Fig. 3c) and not correlated with topoisomerase I (Topo I) inhibition
Summary
DNA replication inhibitors are utilized extensively in studies of molecular biology and as chemotherapy agents in clinical settings. Cells were treated with CPT, coptisine and berberine, and Topo I-DNA covalent complexes were visualized by immunoblotting using an anti-Topo I antibody. Treatment with CPT induced the accumulation of Topo I-DNA covalent complexes, but neither coptisine nor berberine prompted the accumulation of Topo I-DNA complexes (Fig. 3d, Supplementary Fig. 6c).
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