Effects of β- and γ-carboline derivatives on DNA topoisomerase activities

Funayama, Yasunori; Nishio, Kazuto; Wakabayashi, Keiji; Nagao, Minako; Shimoi, Kayoko; Ohira, Tatsuo; Hasegawa, Shizuo; Saijo, Nagahiro

doi:10.1016/0027-5107(95)00176-x

Cited by 124 publications

(67 citation statements)

References 21 publications

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“…We do note that improvement in survival with harmine combinations did not occur, in spite of significant reductions in parasitemia, most likely due to the virulent nature of the P. berghei ANKA strain infection in BALB/c mice. A limitation of this work is that we cannot completely rule out secondary targets such as androgen receptors, topoisomerase I, and DNA excision-repair proteins, because they retain similar GHKL ATP-binding domains (11,16,19). For example, betacarbolines have inhibited topoisomerase activity and DNA excision repair (16,17,25).…”

Section: Fig 3 Plasmodium Berghei Mouse Model Parasitemia Changes In mentioning

confidence: 99%

“…A limitation of this work is that we cannot completely rule out secondary targets such as androgen receptors, topoisomerase I, and DNA excision-repair proteins, because they retain similar GHKL ATP-binding domains (11,16,19). For example, betacarbolines have inhibited topoisomerase activity and DNA excision repair (16,17,25). Harman was also shown to induce the mRNA, protein, and activity levels of the carcinogen-activating enzyme by androgen hydrocarbon receptor (AhR)-mediated signaling; however, it was a weak ligand of AhR (12).…”

Section: Fig 3 Plasmodium Berghei Mouse Model Parasitemia Changes In mentioning

confidence: 99%

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Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Shahinas

MacMullin

Benedict

et al. 2012

Antimicrob Agents Chemother

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Previous studies have shown an antimalarial effect of total alkaloids extracted from leaves of Guiera senegalensis from Mali in West Africa. We independently observed that the beta-carboline alkaloid harmine obtained from a natural product library screen inhibited Plasmodium falciparum heat shock protein 90 (PfHsp90) ATP-binding domain. In this study, we confirmed harmine-PfHsp90-specific affinity using surface plasmon resonance analysis (dissociation constant [K d ] of 40 M). In contrast, the related compound harmalol bound human Hsp90 (HsHsp90) (K d of 224 M) more tightly than PfHsp90 (K d of 7,010 M). Site-directed mutagenesis revealed that Arg98 in PfHsp90 is essential for harmine selectivity. In keeping with our model indicating that Hsp90 inhibition affords synergistic combinations with existing antimalarials, we demonstrated that harmine potentiates the effect of chloroquine and artemisinin in vitro and in the Plasmodium berghei mouse model. These findings have implications for the development of novel therapeutic combinations that are synergistic with existing antimalarials.

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Section: Fig 3 Plasmodium Berghei Mouse Model Parasitemia Changes In mentioning

confidence: 99%

Section: Fig 3 Plasmodium Berghei Mouse Model Parasitemia Changes In mentioning

confidence: 99%

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Shahinas

MacMullin

Benedict

et al. 2012

Antimicrob Agents Chemother

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“…Furthermore, alkaloids such as vinblastine, vincristine and ellipticine have been used as potent anticancer agents (19). Tumor cells were killed by these alkaloids via different mechanisms, such as induction of apoptosis and inhibition of topoisomerase I and II (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Growth Inhibitory Impact of Peganum harmala L. on Two Breast Cancer Cell Lines

et al. 2014

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Background: ß-carbolines, harmaline and harmine, are major alkaloids present in the seeds of Peganum harmala L. These alkaloids are known as herbal active principals with potential use in pharmaceutical and medicine. Objectives: To assess the growth inhibitory effect of phyto-alkaloids, harmaline and harmine, on cancer cell lines. Materials and Methods: P. harmala L.'s alkaloids were extracted by acidic/basic extraction method and identified by two methods, Fourier Transform Infra-Red Spectroscopy (FTIR) and High Performance Liquid Chromatography (HPLC). Two breast cancer cell lines, MDA-MB-231 and Mcf-7, were subjected to different concentrations (1-100 μg.mL -1 ) of the P. harmala extract at different time courses (24, 48, and 72 hours). Methylthiazol Tetrazolium (MTT) test, half maximal inhibitory concentration (IC 50 ) and morphological changes through optical microscopy were evaluated. Results: In both studied cell lines, the P. harmala extract decreased cell viability in longer time exposure in a dose dependent manner. The more concentrated extract led to higher motility of MDA-MB-231 at 24 hours. Although, Mcf-7 cell line required longer exposure time to reach the same motility. It was observed that 30 μg.mL -1 is the minimum lethal dose that kills approximately 50% of cells at 24 hours for MDA-MB-231 cell line (IC 50 ). IC 50 for Mcf-7 was calculated 40 μg.mL -1 and 25 μg.mL -1 48 and 72 hours after being exposed against harmala's extract, respectively. The morphological observation confirmed the apoptosis nature of P. harmala on cells as their membrane kept intact and no membrane permeabilization was observed. Conclusions:The results revealed that the P. harmala extracts significantly decreased the growth rate and cell survival of cancer cell lines. The extract induced cell death regarding natural cell growth rate. MDA-MB-231 cell line naturally has a higher growth rate than Mcf-7 cell line, thus higher growth inhibition of MDA-MB-231 cell line by the P. harmala extract was confirmed.

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“…These alkaloids possess a broad range of pharmacological activities, including anxiolytic and behavioural effects (Murray & Berger, 1997), binding to serotonin and benzodiazepine receptors (Glennon et al, 2000) and inhibitory action of several enzyme reactions (Funayama et al, 1996;Kim et al, 1997;Song et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural changes induced in HeLa cells after phototoxic treatment with harmine

Pérez-Martı́n

Labrador

Freire

et al. 2004

J of Applied Toxicology

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In the present work, we have continued our studies on harmine phototoxicity in human tumour cells. The toxicity of harmine in the dark was analysed by a quantitative neutral red uptake assay, and subcellular sensitive targets following harmine photosensitization were de fi ned by electron microscopic analysis of HeLa cells. The results obtained indicated that this compound shows a clear dose-dependent cytotoxic effect in the dark. The combined treatment with suitable doses of harmine and UV radiation was very effective at an early stage, although maximal cell killing appeared 48 h after photodynamic activation. Ultrastructural examination of HeLa cells immediately after the photodynamic treatment revealed lysosomal destabilization and profound cytoplasmic vacuolization that evolved to cytolysis, which is typical of necrotic cell death. It is concluded that harmine could be a valuable photosensitizer whose biological applications merit further evaluation.

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Effects of β- and γ-carboline derivatives on DNA topoisomerase activities

Cited by 124 publications

References 21 publications

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Harmine Is a Potent Antimalarial Targeting Hsp90 and Synergizes with Chloroquine and Artemisinin

Growth Inhibitory Impact of Peganum harmala L. on Two Breast Cancer Cell Lines

Ultrastructural changes induced in HeLa cells after phototoxic treatment with harmine

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