Berberine Induces Apoptotic Cell Death via Activation of Caspase-3 and -8 in HL-60 Human Leukemia Cells: Nuclear Localization and Structure-Activity Relationships

Shinya Okubo, Takuhiro Uto, Aya Goto, Hiroyuki Tanaka, Tsuyoshi Nishioku, Katsushi Yamada, Yukihiro Shoyama

Research output: Contribution to journalArticle

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Abstract

Berberine (BBR), an isoquinoline alkaloid, is a well-known bioactive compound contained in medicinal plants used in traditional and folk medicines. In this study, we investigated the subcellular localization and the apoptotic mechanisms of BBR were elucidated. First, we confirmed the incorporation of BBR into the cell visually. BBR showed antiproliferative activity and promptly localized to the nucleus from 5min to 15min after BBR treatment in HL-60 human promyelocytic leukemia cells. Next, we examined the antiproliferative activity of BBR (1) and its biosynthetically related compounds (2-7) in HL-60 cells. BBR exerted strongest antiproliferative activity among 1-7 and the results of structures and activity relation suggested that a methylenedioxyl group in ring A, an O-alkyl group at C-9 position, and the frame of isoquinoline may be necessary for antiproliferative activity. Moreover, BBR showed the most potent antiproliferative activity in HL-60 cells among human cancer and normal cell lines tested. Next, we examined the effect of BBR on molecular events known as apoptosis induction. In HL-60 cells, BBR induced chromatin condensation and DNA fragmentation, and triggered the activation of PARP, caspase-3 and caspase-8 without the activation of caspase-9. BBR-induced DNA fragmentation was abolished by pretreatment with inhibitors against caspase-3 and caspase-8, but not against caspase-9. ERK and p38 were promptly phosphorylated after 15 min of BBR treatment, and this was correlated with time of localization to the nucleus of BBR. These results demonstrated that BBR translocated into nucleus immediately after treatments and induced apoptotic cell death by activation of caspase-3 and caspase-8.

Original languageEnglish
Pages (from-to)1497-1511
Number of pages15
JournalAmerican Journal of Chinese Medicine
Volume45
Issue number7
DOIs
Publication statusPublished - Jan 1 2017

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Berberine
Caspase 8
Structure-Activity Relationship
Caspase 3
Leukemia
Cell Death
HL-60 Cells
Caspase 9
Traditional Medicine
DNA Fragmentation
Berberine Alkaloids
Medicinal Plants
Chromatin

All Science Journal Classification (ASJC) codes

  • Complementary and alternative medicine

Cite this

Berberine Induces Apoptotic Cell Death via Activation of Caspase-3 and -8 in HL-60 Human Leukemia Cells : Nuclear Localization and Structure-Activity Relationships. / Okubo, Shinya; Uto, Takuhiro; Goto, Aya; Tanaka, Hiroyuki; Nishioku, Tsuyoshi; Yamada, Katsushi; Shoyama, Yukihiro.

In: American Journal of Chinese Medicine, Vol. 45, No. 7, 01.01.2017, p. 1497-1511.

Research output: Contribution to journalArticle

Okubo, Shinya ; Uto, Takuhiro ; Goto, Aya ; Tanaka, Hiroyuki ; Nishioku, Tsuyoshi ; Yamada, Katsushi ; Shoyama, Yukihiro. / Berberine Induces Apoptotic Cell Death via Activation of Caspase-3 and -8 in HL-60 Human Leukemia Cells : Nuclear Localization and Structure-Activity Relationships. In: American Journal of Chinese Medicine. 2017 ; Vol. 45, No. 7. pp. 1497-1511.
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T2 - Nuclear Localization and Structure-Activity Relationships

AU - Okubo, Shinya

AU - Uto, Takuhiro

AU - Goto, Aya

AU - Tanaka, Hiroyuki

AU - Nishioku, Tsuyoshi

AU - Yamada, Katsushi

AU - Shoyama, Yukihiro

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AB - Berberine (BBR), an isoquinoline alkaloid, is a well-known bioactive compound contained in medicinal plants used in traditional and folk medicines. In this study, we investigated the subcellular localization and the apoptotic mechanisms of BBR were elucidated. First, we confirmed the incorporation of BBR into the cell visually. BBR showed antiproliferative activity and promptly localized to the nucleus from 5min to 15min after BBR treatment in HL-60 human promyelocytic leukemia cells. Next, we examined the antiproliferative activity of BBR (1) and its biosynthetically related compounds (2-7) in HL-60 cells. BBR exerted strongest antiproliferative activity among 1-7 and the results of structures and activity relation suggested that a methylenedioxyl group in ring A, an O-alkyl group at C-9 position, and the frame of isoquinoline may be necessary for antiproliferative activity. Moreover, BBR showed the most potent antiproliferative activity in HL-60 cells among human cancer and normal cell lines tested. Next, we examined the effect of BBR on molecular events known as apoptosis induction. In HL-60 cells, BBR induced chromatin condensation and DNA fragmentation, and triggered the activation of PARP, caspase-3 and caspase-8 without the activation of caspase-9. BBR-induced DNA fragmentation was abolished by pretreatment with inhibitors against caspase-3 and caspase-8, but not against caspase-9. ERK and p38 were promptly phosphorylated after 15 min of BBR treatment, and this was correlated with time of localization to the nucleus of BBR. These results demonstrated that BBR translocated into nucleus immediately after treatments and induced apoptotic cell death by activation of caspase-3 and caspase-8.

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