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

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,...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e25dffc15303468893e8fa92c6174e41
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spelling	oai:doaj.org-article:e25dffc15303468893e8fa92c6174e412021-12-02T18:15:24ZThe benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants10.1038/s41598-021-87344-22045-2322https://doaj.org/article/e25dffc15303468893e8fa92c6174e412021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87344-2https://doaj.org/toc/2045-2322Abstract 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.Naomi InoueTakeshi TerabayashiYuri Takiguchi-KawashimaDaisuke FujinamiShigeru MatsuokaMasanori KawanoKazuhiro TanakaHiroshi TsumuraToshimasa IshizakiHisashi NaraharaDaisuke KohdaYoshihiro NishidaKatsuhiro HanadaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants
description	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.
format	article
author	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
author_facet	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
author_sort	Naomi Inoue
title	The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants
title_short	The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants
title_full	The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants
title_fullStr	The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants
title_full_unstemmed	The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants
title_sort	benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase i mutants
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e25dffc15303468893e8fa92c6174e41
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The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants

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