Structure−Activity Requirements for Flavone Cytotoxicity and Binding to Tubulin

Beutler, John A.; Hamel, Ernest; Vlietinck, A. J.; Haemers, Achiel; Rajan, Padinchare; Roitman, James N.; Cardellina, John H.; Boyd, Michael R.

doi:10.1021/jm970842h

Cited by 130 publications

(87 citation statements)

References 45 publications

(99 reference statements)

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“…Interestingly, it was found that artemetin (3), a close analogue of centaureidin (1), is inactive, and casticin (2) (IC 50 1.286-3.582 μM) containing 3′-hydroxy and 3-methoxy groups, is one order of magnitude less active than centaureidin (1). This finding is in accordance with the observation by Beutler et al (1998) that hydroxy substituents on C-3′ and C-5, and methoxy groups on C-3 and C-4′ are necessary for maximum cytotoxic potency. Casticin (2) reported as a tubulin binding agent and the consequent disturbance in the synthesis of mitotic spindles results in the arrest of cell cycle in G2/M phase.…”

Section: Resultssupporting

confidence: 93%

Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines

Csupor-Löffler

Hajdú

Zupkó

et al. 2008

Phytotherapy Research

108

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The antiproliferative activities of n-hexane, chloroform, aqueous-methanol and aqueous extracts of the aerial parts of the Achillea millefolium aggregate on three human tumour cell lines were investigated by means of MTT assays. The chloroform-soluble extract exerted high tumour cell proliferation inhibitory activities on HeLa and MCF-7 cells, and a moderate effect on A431 cells; accordingly, it was subjected to detailed bioactivity-guided fractionation. As a result of the multistep chromatographic purifications (VLC, CPC, PLC, gel filtration), five flavonoids (apigenin, luteolin, centaureidin, casticin and artemetin) and five sesquiterpenoids (paulitin, isopaulitin, psilostachyin C, desacetylmatricarin and sintenin) were isolated and identified by spectroscopic methods. The antiproliferative assay demonstrated that centaureidin is the most effective constituent of the aerial parts of yarrow: high cell growth inhibitory activities were observed especially on HeLa (IC(50) 0.0819 microm) and MCF-7 (IC(50) 0.1250 microm) cells. Casticin and paulitin were also highly effective against all three tumour cell lines (IC(50) 1.286-4.76 microm), while apigenin, luteolin and isopaulitin proved to be moderately active (IC(50) 6.95-32.88 microm). Artemetin, psilostachyin C, desacetylmatricarin and sintenin did not display antiproliferative effects against these cell lines. This is the first report on the occurrence of seco-pseudoguaianolides (paulitin, isopaulitin and psilostachyin C) in the Achillea genus.

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Section: Resultssupporting

confidence: 93%

Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines

Csupor-Löffler

Hajdú

Zupkó

et al. 2008

Phytotherapy Research

108

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“…It has been identified that the C-3 and C-4' methoxy and C-3' and C-5 hydroxy functional groups provide the strong anti-proliferative activity of this flavonoid (18). Casticin exhibits weaker cytotoxicity but greater selectivity than taxol, (the IC 50 of taxol for tumor cells is at the nmol/l level, while the IC 50 of casticin is at the µmol/l level) (19). Although casticin has little or no effect on the apoptosis of normal cells and tissues, it is reported to have an inhibitory effect on the proliferation of malignant tumors (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells

Yang

Huang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The present study investigated the effect of casticin on reversion-inducing-cysteine-rich protein with kazal motifs (RECK) gene expression and intracellular methylation levels in MGC803 gastric cancer cells. Cells were treated with 1, 10 and 30 µmol/l casticin. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were performed to determine the protein expression and mRNA levels of RECK and DNA methyltransferase 1 (DNMT1), respectively. High-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry was used to detect RECK methylation. In addition, MGC803 cell proliferation was measured by an MTT assay and the DNA-binding activity of transcription factor Sp1 was determined using an enzyme-linked immunosorbent assay. The results demonstrated that treatment with 1, 10 and 30 µmol/l casticin significantly increased RECK protein expression and mRNA levels. In addition, casticin (30 µmol/l) decreased RECK promoter methylation levels by 31%, global DNA methylation levels by 39% and nuclear methylation activity by 71.6%. Furthermore, casticin downregulated the mRNA levels and protein expression of DNMT1. The MTT assay demonstrated that MGC803 cell proliferation was inhibited by casticin treatment and DNA binding assays indicated that casticin reduced the DNA-binding activity of Sp1. The present study therefore indicated that casticin inhibits the proliferation of gastric cancer MGC803 cells by upregulating RECK gene expression and reducing intracellular methylation levels.

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“…Conversely, the presence of a methoxyl group in C-4′ (R3) decreases the toxicity for Vero cells because 3,4′-DMK is less toxic than 3-MK. Beutler et al (1998) compared the cytotoxicity of two flavones on 60 human tumoural strains; 3′-hydroxyl 4′-methoxyl was sixfold more toxic than 3′-methoxyl 4′-hydroxyl. Thus, the nature of the group in C-3′ (R2) and in C-4′ (R3) seems to determine toxicity.…”

Section: Discussionmentioning

confidence: 99%

Antipoliovirus Flavonoids from Psiadia Dentata

Robin¹,

Irurzun

Amoros³

et al. 2001

Antivir Chem Chemother

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The search for antiviral agents against vesicular stomatitis virus, herpes simplex virus type 1 and poliovirus type 2 in plants extracts, led to the isolation of two antipoliovirus flavonoids from the medicinal plant Psiadia dentata (Cass.) DC, Asteraceae: 3-methylkaempferol and 3,4′-dimethylkaempferol. The antipoliovirus activity of both compounds was estimated by comparison with 3-methylquercetin, guanidine and Ro-090179. The most potent inhibitor of poliovirus replication was 3-methylkaempferol, and therefore we investigated its mechanism of action. We showed, using the inhibition of [ 3 H]uridine incorporation in viral RNA and performing a dot-blot with one RNA probe specific for the poliovirus genomic strand RNA, that 3-methylkaempferol inhibits the genomic RNA synthesis of poliovirus.

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Structure−Activity Requirements for Flavone Cytotoxicity and Binding to Tubulin

Cited by 130 publications

References 45 publications

Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines

Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell lines

Casticin inhibits the activity of transcription factor Sp1 and the methylation of RECK in MGC803 gastric cancer cells

Antipoliovirus Flavonoids from Psiadia Dentata

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