Antitumor activity of 13-methyl-berberrubine derivatives.

Ikekawa, Tetsuro; Ikeda, Yoshiaki

doi:10.1248/bpb1978.5.469

Cited by 32 publications

(21 citation statements)

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“…These results are well consistent with the previous reports that berberrubine is a much more potent poison of topoisomerase II than berberine . Furthermore, it has been shown that berberrubine had a strong antitumor activity in mouse models, but berberine had no antitumor activity (Ikekawa and Ikeda, 1982). Berberrubine has a hydroxyl group at the 9-position, whereas berberine contains a methoxy group at this position.…”

Section: Discussionmentioning

confidence: 99%

“…Despite much resemblance in chemical structure, other protoberberine alkaloids such as berberine and palmatine did not act on topoisomerase II. Furthermore, it has been shown that berberrubine and its derivatives exhibit antitumor activity in mouse models, and a hydroxyl group at the 9-position of berberrubine is essential for the manifestation of antitumor activity (Ikekawa and Ikeda, 1982).…”

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confidence: 99%

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Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Kang

Chung

2002

Mol Pharmacol

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Berberrubine, a protoberberine alkaloid that exhibits antitumor activity in animal models, has been identified as a specific poison of DNA topoisomerase II in vitro. To better understand the mechanisms of cellular response to berberrubine, human colorectal carcinoma cells (AMC5) were selected for resistance to berberrubine. The resulting cell line (AMC5/B1) was 5.3-fold resistant to berberrubine in the absence of MDR1 overexpression. The AMC5/B1 line was cross-resistant to topoisomerase II-targeted drugs but showed no cross-resistance to other antitumor drugs. The patterns of cross-resistance to various drugs led us to examine the cellular contents of topoisomerase II. Topoisomerase II activity was ϳ2.8-fold lower in AMC5/B1 cells compared with parental cells. The AMC5/B1 line contained ϳ5-fold decrease in topoisomerase II␣ protein level and ϳ2.5-fold decrease in topoisomerase II␣ mRNA level. A comparison of the degradation kinetics of topoisomerase II␣ mRNA demonstrated that there was no difference in mRNA stability between the two cell lines. Furthermore, the activity of topoisomerase II␣ promoter in AMC5/B1 cells was about 25% of that in AMC5 parental cells when transient transfection experiments were performed with the promoter-luciferase reporter gene. These results indicate that down-regulation of topoisomerase II␣ in AMC5/B1 cells occurs at the transcriptional level. Nucleotide sequencing of the topoisomerase II␣ promoter regions revealed no mutations in AMC5/B1 cells. In summary, resistance to berberrubine in AMC5 cells is associated with decreased level of catalytically active topoisomerase II␣, suggesting that topoisomerase II␣ is the cellular target of berberrubine in vivo.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Kang

Chung

2002

Mol Pharmacol

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“…15,16,17 In this report, we present detailed NMR studies for both berberine and berberrubine related with their biological activities by two dimensional nuclear magnetic resonance (NMR) spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

NMR Studies on Antitumor Drug Candidates, Berberine and Berberrubine

2002

Bulletin of the Korean Chemical Society

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Berberine and berberrubine, which display antitumor activity, have also demonstrated distinct enzymepoisoning activities by stabilizing topoisomerase II-DNA cleavable complexes. The protoberberine berberrubine differs in chemical structure with berberine at only one position, however, it shows a prominent activity difference from berberine. Solution structures of berberine and berberrubine determined by NMR spectroscopy are similar, however, the minor structural rearrangement has been observed near 19 methoxy or hydroxyl group. We suggest that the DNA cleavage activities of topoisomerase II poisons could be correlated with both chemical environments and minor structural change together with hydrophobicity of interacting side chains of drugs with DNA molecule.

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“…16 Furthermore, it has been shown that berberrubine and its derivatives exhibit antitumor activity in mouse models, and a hydroxyl group at the 19-position of berberrubine is essential for the manifestation of antitumor activity. 17 However, the mechanism of action of these drugs that target topoisomerase II is much less clear. Their reported experimental result and suggested mechanism (an intercalation or a groove binding) is still controversial.…”

Section: Introductionmentioning

confidence: 99%

DNA Binding Mode of the Isoquinoline Alkaloid Berberine with the Deoxyoligonucleotide d(GCCGTCGTTTTACA)₂

Park

Kim

Sung

et al. 2004

Bulletin of the Korean Chemical Society

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The ability of protoberberine alkaloids, berberine and berberrubine, to act as topoisomerase II poisons is linked to the anti-cancer activity. Minor alterations in structure have a significant effect on their relative activity. Berberine, which has methoxy group at the 19-position, is significantly less potent than berberrubine. Several observations support non-specific binding to HP14 by the berberine: (i) nonspecific upfield changes in 1 H chemical shift for protons of the berberine; (ii) the broadening of imino protons of HP14 upon binding of the berberine; (iii) very small increases in duplex melting temperature in the presence of the berberine. Our results reveal that substitution of a hydroxyl group to a methoxy group on the 19-position, thereby converting the berberrubine to the berberine is associated with a non-specific DNA binding affinity and a reduced topoisomerase II poisoning. The presence of a bulky 19-methoxy substituent decreases intercalating properties of berberine and makes it inactive as topoisomerase II poison.

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Antitumor activity of 13-methyl-berberrubine derivatives.

Cited by 32 publications

References 2 publications

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

NMR Studies on Antitumor Drug Candidates, Berberine and Berberrubine

DNA Binding Mode of the Isoquinoline Alkaloid Berberine with the Deoxyoligonucleotide d(GCCGTCGTTTTACA)₂

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Antitumor activity of 13-methyl-berberrubine derivatives.

Cited by 32 publications

References 2 publications

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

Down-Regulation of DNA Topoisomerase IIα in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine

NMR Studies on Antitumor Drug Candidates, Berberine and Berberrubine

DNA Binding Mode of the Isoquinoline Alkaloid Berberine with the Deoxyoligonucleotide d(GCCGTCGTTTTACA)2

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DNA Binding Mode of the Isoquinoline Alkaloid Berberine with the Deoxyoligonucleotide d(GCCGTCGTTTTACA)₂