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PubMed1994

The effects of coumarin and suramin on the growth of malignant renal and prostatic cell lines.

Coumarin is known to exert an anti-neoplastic action in patients with malignant melanoma and renal cell carcinoma. We examined the effects of various concentrations (0, 10, 50, 100, 250, 500 micrograms/ml) of coumarin on the proliferation of two renal cell carcinoma cell lines (786-O and A-498) and two malignant prostatic cell lines (DU145 and LNCaP). After 5 days of treatment, coumarin inhibited the growth of the four cell lines. The LNCaP prostatic cell line was more sensitive than the other cell lines to the inhibitory effects of coumarin. We also examined the effects of various concentrations of suramin (0, 50, 200 and 400 micrograms/ml), and anti-neoplastic compound currently undergoing clinical trials, on the growth of the 786-O and LNCaP cell lines. Both of these were inhibited by suramin at concentrations greater than 100 micrograms/ml. Finally we examined the effects of combined treatment with coumarin and suramin on the growth of LNCaP and 786-O cells. When combined with all concentrations of suramin studied (0, 50, 200 and 400 micrograms/ml), coumarin further inhibited cellular proliferation of the LNCaP and 786-O cell lines. However, the combination of the highest concentration of coumarin (500 micrograms/ml) with suramin at 400 micrograms/ml did not inhibit the proliferation of the cells more than 500 micrograms/ml coumarin alone.

Carcinoma, Renal Cell↗
PubMed2001

Coumarin metabolism by rat esophageal microsomes and cytochrome P450 2A3.

The rat esophagus is strikingly sensitive to tumor induction by nitrosamines, and it has been hypothesized that this tissue contains cytochrome P450 enzymes (P450s) which catalyze the metabolic activation of these carcinogens. The metabolic capacity of the esophagus is not well characterized. In the study described here, the products of 14C-coumarin metabolism by rat esophageal microsomes were identified and quantified. Metabolite characterization was by LC/MS/MS and GC/MS and comparison to standards, quantification was by radioflow HPLC. The coumarin metabolites formed by rat esophageal microsomes were compared to those formed by P450 2A3. The major metabolites formed by esophageal microsomes were 8-hydroxycoumarin, o-hydroxyphenylacetaldehyde (o-HPA), and o-hydroxyphenylacetic acid (o-HPAA). A smaller amount of 5-hydroxycoumarin, about one-third the 8-hydroxycoumarin, was also formed. o-HPA and o-HPAA are products of coumarin 3,4-epoxidation. The relative rates of coumarin 8-hydroxylation and 3,4-epoxidation were similar. Coumarin 8-hydroxylation has not previously been reported as a major pathway in any tissue, and no P450s have yet been reported to catalyze this reaction. P450 2A3 catalyzed both the 7-hydroxylation and 3,4-epoxidation of coumarin. P450 2A3 was previously characterized as a coumarin 7-hydroxylase, however, in this study, we report that it catalyzes the formation of o-HPA more efficiently. The Km and Vmax were 1.3 +/- 0.35 microM and 0.65 +/- 0.06 nmol/min/nmol P450 for coumarin 7-hydroxylation and 1.4 +/- 0.58 microM and 3.1 +/- 0.46 nmol/min/nmol P450 for o-HPA formation.

Animals↗
PubMed2005

Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis.

Cytochrome P450 (P450) 2A6 is an important human enzyme involved in the metabolism of many xenobiotic chemicals including coumarin, indole, nicotine, and carcinogenic nitrosamines. A combination of random mutagenesis and high-throughput screening was used in the analysis of P450 2A6, utilizing a fluorescent coumarin 7-hydroxylation assay. The steady-state kinetic parameters (k(cat) and Km) for coumarin 7-hydroxylation by wild-type P450 2A6 and 35 selected mutants were measured and indicated that mutants throughout the coding region can have effects on activity. Five mutants showing decreased catalytic efficiency (k(cat)/Km) were further analyzed for substrate selectivity and binding affinities and showed reduced catalytic activities for 7-methoxycoumarin O-demethylation, tert-butyl methyl ether O-demethylation, and indole 3-hydroxylation. All mutants except one (K476E) showed decreased coumarin binding affinities (and also higher Km values), indicating that this is a major basis for the decreased enzymatic activities. A recent x-ray crystal structure of P450 2A6 bound to coumarin (Yano, J. K., Hsu, M. H., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2005) Nat. Struct. Mol. Biol. 12, 822-823) indicates that the recovered A481T and N297S mutations appear to be close to coumarin, suggesting direct perturbation of substrate interaction. The decreased enzymatic activity of the K476E mutant was associated with decreases both in NADPH oxidation and the reduction rate of the ferric P450 2A6-coumarin complex. The attenuation is caused in part to lower binding affinity for NADPH-P450 reductase, but the K476E mutant did not achieve the wild-type coumarin 7-hydroxylation activity even at high reductase concentrations.

Amino Acid Sequence↗
PubMed2003

CYP2A13-catalysed coumarin metabolism: comparison with CYP2A5 and CYP2A6.

1. We investigated the total metabolism of coumarin by baculovirus (BV)-expressed CYP2A13 and compared it with metabolism by BV-expressed CYP2A6. The major coumarin metabolite formed by CYP2A13 was 7-hydroxycoumarin, which accounted for 43% of the total metabolism. The product of 3,4-epoxidation, o-hydroxyphenylacetaldehyde (o-HPA), accounted for 30% of the total metabolites. 2. The K(m) and V(max) for CYP2A13-mediated coumarin 7-hydroxylation were 0.48+/-0.07 micro m and 0.15+/-0.006 nmol min(-1) nmol(-1) CYP, respectively. The V(max) of coumarin 7-hydroxylation by CYP2A13 was about 16-fold lower than that of CYP2A6, whereas the K(m) was 10-fold lower. 3. In the mouse, there were two orthologues for CYP2A6: CYP2A4 and CYP2A5, which differed by only 11 amino acids. However, CYP2A5 is an efficient coumarin 7-hydroxylase, where as CYP2A4 is not. We report here that BV-expressed CYP2A4 metabolizes coumarin by 3,4-epoxidation. Two products of the 3,4-epoxidation pathway, o-HPA and o-hydroxyphenylacetic acid (o-HPAA), were detected by radioflow HPLC. 4. The K(m) and V(max) for the coumarin 3,4-epoxidation by CYP2A4 were 8.7+/-3.6 micro m and 0.20+/-0.04 nmol min(-1) nmol(-1) CYP, respectively. Coumarin 7-hydroxylation by CYP2A5 was more than 200 times more efficient than 3,4 epoxidation by CYP2A4.

Animals↗
PubMed1996

Metabolism and toxicity of coumarin on cultured human, rat, mouse and rabbit hepatocytes.

We compared the cytotoxic effect of coumarin and its derivatives, 7-hydroxycoumarin (7-OHC), 4-hydroxycoumarin (4-OHC), o-hydroxyphenyl acetic acid (OHPAA) and o-coumaric acid (CA), on cultured hepatocytes from human, rat, mouse and rabbit liver. At 10(-5) and 5 x 10(-5) M, coumarin and its derivatives did not give rise to any signs of toxicity on cultured hepatocytes of the four species. At 10(-4) M, coumarin, but not its derivatives, induced release of lactate dehydrogenase (LDH) into the medium, especially in rat hepatocyte cultures. Intracellular LDH activities were correspondingly reduced. The cytotoxic effect of coumarin in cultured rat hepatocytes was evidenced on morphological examination and from the results of the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium (MTT) reduction test. At higher concentrations (5 x 10(-4) M), 7-OHC and CA were also found to be cytotoxic in cultured rat hepatocytes. The cytotoxic effect of coumarin (5 x 10(-4) M) was decreased in the presence of SKF 525-A, a cytochrome P450 inhibitor. Interspecies comparisons showed that rat hepatocytes were the most sensitive to the toxicity of coumarin and its derivatives, whereas human hepatocytes were the most resistant. Our results suggest that the cytotoxicity of coumarin is metabolism and species-dependent. Thus, the rat may not be a suitable model for evaluating the pharmacological hazards of coumarin in humans.

4-Hydroxycoumarins↗
PubMed2002

Costs and effectiveness of using coumarins before, during and after coronary angioplasty.

BACKGROUND: In the Balloon Angioplasty and Anticoagulation Study (BAAS), coumarins added to routine aspirin therapy before coronary angioplasty reduced cardiac events at the cost of a slightly higher risk of bleeding complications. OBJECTIVE: To determine the cost effectiveness of coumarin treatment, based on the occurrence of both cardiac and bleeding events. METHODS: Effectiveness was measured, applying two definitions, in terms of the number of events occurring at one year. In the first definition, the occurrence of death, myocardial infarction (MI), or stroke was assessed. The second definition also included revascularisations and major bleeding episodes as an event. Costs were limited to direct medical costs. Cost effectiveness was addressed by probability ellipses representing the point estimates and uncertainties surrounding both costs and effectiveness. RESULTS: At 1 year, death, MI or stroke occurred 1.1% less often when treating with aspirin plus coumarins rather than aspirin therapy alone. When revascularisations and major bleeding events were also included, the difference was 5.0%. Overall, the additional costs in relation to coumarin treatment were compensated by a reduction in repeat interventions. When including all costs, the savings associated with coumarin treatment were estimated at Euros 235 per patient after 1 year. The probability that coumarins are cost saving was estimated at 0.85. The probability that coumarins combine additional effectiveness with cost savings was estimated at 0.70 when survival free of MI or stroke as an effectiveness measure was considered, and at 0.83 when survival free of MI, stroke, revascularisation or major bleeding was considered. CONCLUSION: Coumarin therapy added to routine aspirin therapy before coronary angioplasty, and continued during follow-up, may not only be considered more effective but also cost saving relative to aspirin therapy alone.

Angioplasty, Balloon, Coronary↗
PubMed2005

Synthetic and natural coumarins as cytotoxic agents.

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their cytotoxic effects were most extensively examined. In this review, their broad range of effects on the tumors as shown by various in vitro and in vivo experiments and clinical studies are discussed. Hence, these cytotoxic coumarins represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. In this review, plant derived coumarins and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy. Owing the their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins, used as cytotoxic agents, because promising data have been reported for a series of these agents. Yet, the results from different coumarins with various tumor lines are contradictory in part. We therefore conclude that there is still a long way to go until we know which cytotoxic agent will clinically be suitable for what tumor entity for treatment. Their ability to bind metal ions represents an additional means of modulating their pharmacological responses.

Animals↗
PubMed1999

Biotransformation of coumarin by rodent and human cytochromes P-450: metabolic basis of tissue-selective toxicity in olfactory mucosa of rats and mice.

Coumarin was previously found to cause tissue-selective toxicity in the olfactory mucosa (OM) of rats and mice, with rats being the more sensitive species. The aim of this study was to explore the role of target tissue biotransformation in OM-selective toxicity and the metabolic basis of the species differences in coumarin toxicity. At least six coumarin metabolites were detected in OM microsomal reactions, with o-hydroxyphenylacetaldehyde (o-HPA) being the most abundant. Formation of o-HPA was inhibited by reduced glutathione, confirming its origin from a reactive intermediate. There were significant differences in the rates and metabolite profiles of coumarin metabolism in the livers of Wistar rats and C57BL/6 mice. The rates of metabolic activation of coumarin, as indicated by the formation of o-HPA, were comparable in OM microsomes of the two species but about 25- and 3-fold higher in OM than in liver microsomes of rats and mice, respectively. Thus, target tissue activation seems to play an important role in the tissue-selective toxicity, whereas differences in the rates of hepatic metabolism may be responsible for the species difference in olfactory toxicity. Purified, heterologously expressed mouse CYP2A5 and CYP2G1 produced 7-hydroxycoumarin and o-HPA as the predominant products, respectively. Kinetic analysis and immunoinhibition studies indicated that the OM-specific CYP2G1 plays the major role in metabolic activation of coumarin. Furthermore, of 13 human cytochrome P-450s (P-450s) examined, five (CYP1A1, CYP1A2, CYP2B6, CYP2E1, and CYP3A4) were active in the metabolic activation of coumarin, suggesting a potential risk of coumarin toxicity in humans.

Animals↗
PubMed2000

Pronounced differences in inhibition potency of lactone and non-lactone compounds for mouse and human coumarin 7-hydroxylases (CYP2A5 and CYP2A6).

1. The structural requirements for a compound to be a potent inhibitor for mouse CYP2A5 and human CYP2A6 enzymes catalysing coumarin 7-hydroxylase activity have been studied. 2. The IC50 of 28 compounds for the pyrazole-treated male DBA/2 mouse and human liver microsomal coumarin 7-hydroxylation were determined at 10 microm coumarin concentration 15 times over Km of coumarin. 3. The three most potent inhibitors for CYP2A5 were gamma-nonanoic lactone, gamma-decanolactone and gamma-phenyl-gamma-butyrolactone with an IC50 = 1.9+/-0.4, 2.1+/-0.2 and 2.4+/-0.3 microM and for CYP2A67-methylcoumarin, butylcyclohexane and indan with an IC50. = 30+/-3.2, 43+/-9 and 50+/-11 microM. 4. Among the 28 compounds studied, only 2-benzoxazolinone, 2-indanone and gamma-valerolactone showed similar inhibitory activity in both species. Indan had a lower IC50 for human than for mouse coumarin 7-hydroxylation, whereas the IC50 of 24 other compounds was higher for human than for mouse coumarin 7-hydroxylation. 5. The largest difference in IC50 between mouse and human activity was observed with 5-substituted phenyl, pentyl, hexyl, heptyl or octyl gamma-lactones or 6-substituted delta-lactones. IC50 of gamma-undecanolactone and gamma-decanolactone was 500 times lower for mouse than human coumarin 7-hydroxylation. 6. The difference in the IC50 between human and mouse coumarin 7-hydroxylation decreased substantially with the corresponding compounds without the lactone ring. 7. It is concluded that certain 5- or 6-position substituted gamma- and delta-lactones are potent inhibitors for mouse CYP2A5 but not for the orthologous human CYP2A6 and that the active site of CYP2A6 could be smaller than the active site of CYP2A5.

Animals↗
PubMed1977

The value of multifactorial screening for anti-inflammatory activity as shown by coumarin.

Different types of acute inflammatory pleural reactions have been used as a means of detecting the anti-inflammatory potential of a particular drug coumarin. The latter had some type of activity in all the reactions. However, whereas coumarin inhibited leucocyte accumulation induced by dextran it had no effect on the volume of fluid exudate. Conversely, coumarin reduced the volume of exudate in the Arthus reaction whereas the cellular infiltrate remained unaltered. Leucocytes from dextran-induced exudate (predominantly polymorphs) removed from animals pretreated with coumarin showed marked inhibition of migration in vitro. This correlated well with the suppression by coumarin of the dextran-induced leucocyte response in vivo. Coumarin administered in vivo was also shown to stimulate phagocytosis of latex by mouse peritoneal macrophages in vitro. These findings are discussed with respect to the evaluation of anti-inflammatory drug activity and to the mode of action of coumarin.

Animals↗
PubMed1997

Comparative in vitro skin absorption and metabolism of coumarin (1,2-benzopyrone) in human, rat, and mouse.

The in vitro percutaneous absorption and skin metabolism of coumarin (1,2-benzopyrone) was studied in metabolically viable human, rat (F344), and mouse (CD1 and DBA/2) skin. Following application of [14C]coumarin (3.7 microg/cm2; 0.02% in ethanol) to unoccluded skin in flow-through diffusion cells of a skin absorption model (SAM), the absorption through the skin into the receptor fluid at 72 hr was rapid and extensive in all species, reaching (mean +/- SD) 50.4 + 9.1% of the applied dose in human, 51.3 +/- 7.3% in rat, and 44.9 +/- 13.5% in mouse. When the skin was occluded immediately after exposure, the extent of absorption at 72 hr was enhanced in all species. At 72 hr, substantial amounts of [14C]coumarin were found in unoccluded mouse skin (31.7 +/- 13.6%), with less in human (10.2 +/- 6.5%) and rat (12.7 +/- 5.0%) tissue. When occluded, the skin residues at 72 hr were 10.4 +/- 11.7% (mouse), 8.5 +/- 3.9% (human), and 11.9 +/- 7.5% (rat). The absorption of coumarin through rat skin into the receptor fluid over 72 hr was linearly related to the applied dose (r2 = 0.998 unoccluded skin; r2 = 0.999 occluded skin) over the dose range 3.7 to 378.7 microg/cm2. The nature and extent of cutaneous metabolism was studied following (i) topical application for 24 hr to human, rat, and mouse skin in the SAM system; (ii) incubation at 37 degrees C for up to 6 hr with human, rat, and mouse whole skin homogenates; and (iii) incubation at 37 degrees C for up to 24 hr with freshly isolated and cultured human epidermal keratinocytes. HPLC and GCMS analyses of skin extracts and receptor fluid confirmed that, in all three species, only the parent compound, coumarin, was present at all times from 10 min to 24 hr. These data indicate that topically applied coumarin is rapidly and extensively absorbed through human, rat, and mouse skin, and that the compound remains metabolically unchanged during absorption. These observations may have implications for the safe and effective use of coumarin in consumer products which come into contact with the skin and as a topical therapeutic agent.

Aged↗
PubMed1979

A comparison of coumarin and levamisole on parameters of the inflammatory response.

Three experimental animal models have been used in the studies on the stimulatory effect of coumarin and levamisole. Both coumarin and levamisole increases cell coverage on subcutaneous implanted glass coverslip in mice. An increase in intracellular phosphatase activity was also observed. Stimulated mouse peritoneal cells when treated in vivo with coumarin or levamisole and then cultured in vitro showed increases acid phosphatase secretion (both extracellular and intracellular) as compared to control. Coumarin reduced the primary lesion of adjuvant-induced arthritis in rats. However, it potentiates the secondary lesions. Levamisole has no effect on the primary lesion but potentiates the secondary lesions. There was an increase in spleen and adrenal weights which correlate well with the severity of the secondary lesions. Increase in liver weight was only observed in coumarin-treated animals, an observation which suggests that coumarin may be a powerful mononuclear phagocytes system stimulant. The similarities and differences between coumarin and levamisole in their mode of action will be discussed.

Acid Phosphatase↗
PubMed1991

Local beneficial effect of coumarin in experimental peritonitis.

Coumarin, a potent immune stimulant and macrophage activator, has been used to treat brucellosis and as an immune suppressor. The effect of Coumarin and systemic antibiotics on septicaemia, survival and peritoneal contamination in experimental peritonitis was assessed. Four groups of male Sprague-Dawley rats were inoculated with Clostridium perfringens, Escherichia coli and Bacteroides fragilis. Group A received saline alone, Group B received Coumarin alone, Group C received antibiotics (Clindamycin and Cephradine) alone and Group D received both Coumarin and antibiotics. Septicaemia, confirmed by blood culture, occurred in all animals. Coumarin did not improve survival whether given alone or in combination with antibiotics. Animals given Coumarin (Groups B and D) had significantly less peritoneal soiling (54%, 0%) (P less than 0.02, P less than 0.001) than their controls (Groups A and C: 92%; 29%). While Coumarin did not improve resistance to septicaemia it did exert a local beneficial effect.

Animals↗
PubMed1994

Superoxide scavenging activity in leukocytes and absence of cellular toxicity of a series of coumarins.

Sixteen synthetic or plant-derived coumarins of dietary importance with different patterns of substitution were tested for their capacity to scavenge superoxide and for their cytotoxicity. Superoxide was generated by human polymorphonuclear leukocytes stimulated by phorbol myristate acetate and was measured using the reduction of ferricytochrome c or of nitrobule tetrazolium (NBT). Eleven of the coumarins, all lacking dihydroxy substitution, did not scavenge superoxide. Of the remaining five, the most potent scavenger was fraxetin (7,8-dihydroxy-6-methoxycoumarin) with an IC50 (concentration producing 50% inhibition) of 2.3 microM in the cytochrome assay and 5.8 microM using NBT. The other four coumarins (all containing ortho-dihydroxy catechol functions, and found previously to be pro-oxidant in cell-free systems by virtue of reduction of ferric to ferrous ions), themselves rapidly reduced cytochrome c. Therefore their effects on superoxide were measured using NBT, yielding IC50 values in the range 8.5 to 82.0 microM. Fraxetin and the other active and inactive coumarins were not directly cytotoxic at 100 microM to leukocytes or to erythrocytes, as shown by their failure to cause release of cytosolic lactate dehydrogenase or to cause haemolysis, respectively. However, all five dihydroxylated pro-oxidant coumarins were toxic to NS20Y neuroblastoma cells in 24 hr culture, whereas the other eleven coumarins were nontoxic. We conclude that 7,8-dihydroxylated coumarins such as fraxetin are agents which are not themselves directly cytotoxic and are capable of direct scavenging of superoxide anion radicals, an action which might be protective at sites of leukocyte activation during inflammation. However, in the presence of free ferric ions they may exert potentially damaging pro-oxidant actions, including cytotoxicity. This series of compounds provides a useful basis for structure-activity studies designed to achieve separation or combination of these properties.

Animals↗
PubMed1992

Species differences in the hepatotoxicity of coumarin: a comparison of rat and Mongolian gerbil.

The acute hepatic effects of coumarin (2H-1-benzopyran-2-one) in male Wistar rats and Mongolian gerbils has been compared. A single dose of coumarin (125 mg/kg, intraperitoneally (i.p.)) was hepatotoxic to rats within 24 h as assessed by its effects on a variety of hepatic parameters. Coumarin-induced hepatotoxicity was associated with significant increases in relative liver weight, plasma alanine and aspartate aminotransferase activities and hepatic non-protein sulphydryl groups. Cytochrome P-450 content and 7-ethoxycoumarin O-deethylase and glucose 6-phosphatase activities were significantly lower in coumarin-treated compared with control rats. Centrilobular necrosis was only observed in two out of six rats at this dose, but was present in all four coumarin-treated rats when the dose was increased to 150 mg/kg. In contrast to the effects observed in the rat, no evidence was found for coumarin-induced hepatotoxicity in gerbils following a single i.p. dose of 125 mg/kg. These data indicate that the gerbil is less sensitive to the hepatotoxic effects of coumarin than the rat.

Animals↗
PubMed2006

In vitro anti-tumour and cyto-selective effects of coumarin-3-carboxylic acid and three of its hydroxylated derivatives, along with their silver-based complexes, using human epithelial carcinoma cell lines.

The chemotherapeutic potential of coumarin-3-carboxylic acid (C-3-COOH) and a series of three hydroxylated coumarin-3-carboxylic acid ligands, namely 6-hydroxy-coumarin-3-carboxylic acid (6-OH-C-3-COOH), 7-hydroxy-coumarin-3-carboxylic acid (7-OH-C-3-COOH) and 8-hydroxy-coumarin-3-carboxylic acid (8-OH-C-3-COOH), along with their corresponding silver-based complexes, namely 6-hydroxycoumarin-3-carboxylatosilver (6-OH-C-COO-Ag), 7-hydroxycoumarin-3-carboxylatosilver (7-OH-C-COO-Ag) and 8-hydroxycoumarin-3-carboxylatosilver (8-OH-C-COO-Ag), was determined using two human-derived carcinoma (A-498 and Hep-G2), along with two non-carcinoma human-derived cell lines (CHANG and HK-2). All of the ligands and their silver complexes induced a concentration-dependent cytotoxic effect. Furthermore, hydroxylation of C-3-COOH and its subsequent complexation with silver led to the production of a series of compounds with dramatically enhanced cytotoxicity, with 6-OH-C-3-COO-Ag having the greatest activity. Additionally, all of the metal-based complexes were selectively cytotoxic to both carcinoma-derived cell lines, relative to normal renal and hepatic cells. In comparative studies with cisplatin, and based on the IC(50) values obtained with Hep-G2 cells, it appeared that the coumarin-silver complexes were between 2 and 5.5 times more cytotoxic than cisplatin. All of the coumarin-silver complexes inhibited DNA synthesis, which did not appear to be mediated through intercalation. Furthermore, results obtained from Ames tests showed that all of the test agents and their phase I metabolites were non-mutagenic. Taken together, these findings suggest that both hydroxylation particularly in the 6th position and complexation with silver, served to significantly augment the cytotoxic properties of C-3-COOH, to yield a compound which acts as a cyto-selective agent, as it is a significant killer of cancer, relative to normal cells. We suggest that this group of compounds may have a therapeutic role to play in the successful treatment and management of cancer in man.

Antineoplastic Agents↗
PubMed2004

Apoptosis and cell cycle disturbances induced by coumarin and 7-hydroxycoumarin on human lung carcinoma cell lines.

Coumarin and 7-hydroxycoumarin have anti-tumour actions in vitro and in vivo. There are no previous reports on the cytostatic and apoptotic actions of coumarin and 7-hydroxycoumarin in non-small cell lung carcinoma (NSCLC) cell lines. Here we report on: (1) the inhibition of cell proliferation, (2) the phase in which cell cycle arrest occurs, and (3) the induction of apoptosis. Inhibition of cell proliferation was determined by 3H-thymidine incorporation. The effects on cell cycle phases were determined at 100 microg/ml of coumarin or 7-hydroxycoumarin using propidium iodide and flow cytometry. Higher concentrations were used to study apoptosis, detected by: (1) morphological cell changes, (2) subG1 peak detection and (3) Annexin-V assay. Peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin were used as controls. The actions of these compounds depended on drug concentrations and on histological cell type. Coumarin and 7-hydroxycoumarin inhibited cell growth by inducing cell cycle arrest in the G1 phase in all the lung carcinoma cell lines. Apoptosis required large concentrations of the coumarin compounds and was observed in adenocarcinomas. Apoptosis was not associated with intra-nucleosomal DNA fragmentation. Apoptosis was not observed in squamous lung carcinoma cell lines, but an increase in G1 cell cycle arrest was detected. In PBMC, only large concentrations of the coumarin compounds elicited a cystostatic action. Coumarins in combination with other anti-neoplastic drugs might increase the effectiveness of NSCLC treatments.

Adenocarcinoma↗
PubMedDate not supplied

Inhibition and inactivation of murine hepatic ethoxy- and pentoxyresorufin O-dealkylase by naturally occurring coumarins.

The present study was designed to evaluate the effects of a series of natural coumarins on ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in vitro using hepatic tissues from SENCAR mice. Fifteen different coumarins were examined for potential modulating activities. Several naturally occurring coumarins, found in the human diet, were effective inhibitors of hepatic EROD activity in vitro, including coriandrin, bergamottin, isoimperatorin, and ostruthin. Notably, coriandrin and bergamottin were approximately as potent as 7,8-benzoflavone, a relatively selective inhibitor of cytochrome P450 1A1. Several naturally occurring coumarins were also potent inhibitors of hepatic PROD activity, including imperatorin, bergamottin, isopimpinellin, and angelicin. Kinetic studies of the type of inhibition revealed that these compounds inhibited hepatic EROD and PROD activity by a variety of modes rather than by a uniform one. Furthermore, experiments using a two-stage incubation assay revealed that coriandrin, imperatorin, ostruthin, and several other natural coumarins inactivated hepatic EROD activity (i.e., predominantly cytochrome P450 1A1-mediated) and that isopimpinellin inactivated hepatic PROD activity (i.e., predominantly cytochrome P450 2B1-mediated). Finally, the results indicate that some coumarins had selective inhibitory effects for EROD vs PROD and preliminary analyses suggested a possible structural basis for the observed differences. The current data suggest that certain naturally occurring coumarins, to which humans are exposed in the diet, are potent modulators of cytochrome P450. Furthermore, these compounds may be capable of influencing the metabolic activation of other xenobiotics, including chemical carcinogens.

Animals↗