The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants

Naomi Inoue, Takeshi Terabayashi, Yuri Takiguchi-Kawashima, Daisuke Fujinami, Shigeru Matsuoka, Masanori Kawano, Kazuhiro Tanaka, Hiroshi Tsumura, Toshimasa Ishizaki, Hisashi Narahara, Daisuke Kohda, Yoshihiro Nishida, Katsuhiro Hanada

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number7718
JournalScientific reports
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 2021

All Science Journal Classification (ASJC) codes

  • General

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