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At least 19 recordsLinked to original sources
PubMed1984

Inhibition of the biosynthesis of deoxyribonucleic acid, ribonucleic acid and protein in HeLa S3 cells by cucurbitacins, glucocorticoid-like cytotoxic triterpenes.

Cucurbitacins were found to inhibit the incorporation of radioactive precursors into DNA, RNA and protein in intact and permeabilized HeLa S3 cells. The observed inhibition was rapid and irreversible although the maximal effect (almost complete inhibition) required several hours of cell exposition to the agent. The magnitude of the inhibition was, with some exceptions, nearly the same for all three precursors within the entire range of cucurbitacin concentrations examined. The ID50 values (concentrations required to produce half-maximal inhibition of the macromolecule biosynthesis) determined for several cucurbitacins were very close to their respective ED50 values (those for half-maximal inhibition of cell proliferation). Parallel with the inhibition of [3H]-labelled precursor incorporations into nucleic acids, cucurbitacin diminished the [3H]thymidine and [3H]uridine nucleotides' pool sizes of HeLa S3 cells. No effect of cucurbitacin on the [3H]leucine pool was observed. The studies presented prove that cucurbitacins inhibit the biosynthesis of DNA, RNA and protein in HeLa S3 cells, and that these inhibitory effects are closely related to the inhibition of HeLa S3 cell proliferation by cucurbitacins. The mechanism of the inhibition is unknown but the obtained results suggest that cucurbitacins act upon an unidentified target, which results in the inhibition of macromolecule biosynthesis. It was also found that these inhibitory effects of cucurbitacins are neither mediated by glucocorticoid receptors nor require replication, transcription or translation.

Antineoplastic Agents↗
PubMed1996

Cucurbitacin E-induced disruption of the actin and vimentin cytoskeleton in prostate carcinoma cells.

Cucurbitacin E has been identified by an empiric screening strategy as a sterol with potent growth inhibitory activity in vitro directed against prostate carcinoma explants (IC50 of 7-50 nM in 2- to 6-day exposures). The mechanism of cucurbitacin cytoxicity has not been elucidated previously. In the present study, we observed that cucurbitacin E caused marked disruption of the actin cytoskeleton, and in a series of cucurbitacin analogues, anti-proliferative activity correlated directly with the disruption of the F-actin cytoskeleton. The distribution of vimentin was also altered in cells exposed to cucurbitacin E, as vimentin associated with drug-induced membrane blebs. The appearance of microtubules was unaffected. Western blot analysis of intracellular actin in cells exposed to cucurbitacins and quantitation of rhodamine-phalloidin binding support the hypothesis that cucurbitacin treatment leads to an inappropriate increase in the filamentous or polymerized actin fraction in prostate carcinoma cells. We conclude that cucurbitacins are potent disruptors of cytoskeletal integrity. Prostate carcinoma cells appear notably sensitive to growth inhibition by cucurbitacin E.

Actins↗
PubMed1981

Binding of the cytotoxic and antitumor triterpenes, cucurbitacins, to glucocorticoid receptors of HeLa cells.

1. The binding of cucurbitacins to glucocorticoid receptors in HeLa cell-free systems and in intact cells was studied by competition with [3H]cortisol. Cucurbitacins were found to diminish the [3H]cortisol binding. 2. The difference in binding affinity at two temperatures suggest that cucurbitacins are metabolized under physiological conditions. 3. A linear correlation was observed between logarithms of relative binding affinities and of cytotoxic activities of cucurbitacins. Hence, the cucurbitacin binding to glucocorticoid receptors seems to be a necessary step for cytotoxic action of these compounds. 4. Cucurbitacin I was found to form cytoplasmic and nuclear salt-extractable complexes with glucocorticoid receptors of intact HeLa cells at 37 degrees C. Unlike cortisol, cucurbitacin I did not produce salt-resistant nuclear complexes.

Antineoplastic Agents↗
PubMed2026

Cucurbitacins in Plant-Insect Interactions: Biosynthesis, Regulation, Ecological Functions, and Prospects for Crop Protection.

Cucurbitacins are highly oxygenated tetracyclic triterpenoids characterized by intense bitterness, substantial structural diversity, and important consequences for plant-herbivore interactions. Although best known from Cucurbitaceae, cucurbitacins and related cucurbitane-type metabolites also occur in phylogenetically distant herbaceous and woody plants. Genetic and biochemical studies have validated several core biosynthetic steps, including cucurbitadienol formation by oxidosqualene cyclases and subsequent modification by cytochrome P450 monooxygenases, acyltransferases, and glycosyltransferases. Tissue-preferential basic helix-loop-helix transcription factors constitute the best-characterized regulatory layer, whereas the evidence supporting accessory regulators, transporters, and environmental responses varies from functional validation to transcriptomic or genomic prediction. From the plant perspective, cucurbitacins deter feeding or impair performance in many generalist and non-adapted herbivores. By contrast, their use as host-recognition cues and feeding stimulants by specialist diabroticite beetles reflects evolved herbivore adaptations involving perception, tolerance, metabolism, or sequestration rather than a second defensive function of the plant trait. Herbivore-induced cucurbitacin accumulation has been demonstrated in particular systems, although its regulatory mechanisms and ecological generality remain unresolved. Unlike previous reviews centered primarily on cucurbitacin chemistry, pharmacological activity, or individual biosynthetic pathways, this review integrates evidence-graded pathway reconstruction and molecular regulation with taxonomic distribution, insect adaptation, domestication, and agroecological consequences. Mechanistically, this review traces how scaffold formation, oxidative tailoring, conjugation, tissue-specific regulation, and transport give rise to contrasting ecological outcomes through herbivore-specific perception, tolerance, metabolism, and sequestration. We conclude that uniformly increasing or eliminating cucurbitacins is unlikely to provide broadly effective crop resistance because either direction may favor a different herbivore group. Future priorities include functional validation of candidate genes, spatially resolved metabolite analysis, comparative investigation of non-cucurbit lineages, and field evaluation involving generalist and specialist herbivores, crop quality, and non-target organisms. These advances will support context-specific fruit-quality improvement, behavioral pest control, and integrated pest management strategies rather than cucurbitacin manipulation as a stand-alone resistance approach.

agroecology↗
PubMed1997

Cucurbitacins are insect steroid hormone antagonists acting at the ecdysteroid receptor.

Two triterpenoids, cucurbitacins B and D, have been isolated from seeds of Iberis umbellata (Cruciferae) and shown to be responsible for the antagonistic activity of a methanolic extract of this species in preventing the 20-hydroxyecdysone (20E)-induced morphological changes in the Drosophila melanogaster BII permanent cell line. With a 20E concentration of 50 nM, cucurbitacins B and D give 50% responses at 1.5 and 10 microM respectively. Both cucurbitacins are able to displace specifically bound radiolabelled 25-deoxy-20-hydroxyecdysone (ponasterone A) from a cell-free preparation of the BII cells containing ecdysteroid receptors. The Kd values for cucurbitacins B and D (5 and 50 microM respectively) are similar to the concentrations required to antagonize 20E activity with whole cells. Cucurbitacin B (cucB) prevents stimulation by 20E of an ecdysteroid-responsive reporter gene in a transfection assay. CucB also prevents the formation of the Drosophila ecdysteroid receptor/Ultraspiracle/20E complex with the hsp27 ecdysteroid response element as demonstrated by gel-shift assay. This is therefore the first definitive evidence for the existence of antagonists acting at the ecdysteroid receptor. Preliminary structure/activity studies indicate the importance of the Delta23-22-oxo functional grouping in the side chain for antagonistic activity. Hexanorcucurbitacin D, which lacks carbon atoms C-22 to C-27, is found to be a weak agonist rather than an antagonist. Moreover, the side chain analogue 5-methylhex-3-en-2-one possesses weak antagonistic activity.

Animals↗
PubMed2003

Anticancer and antiinflammatory activities of cucurbitacins from Cucurbita andreana.

Bioassay-guided purification of an extract of Cucurbita andreana fruits yielded cucurbitacins B (1), D (2), E (3), and I (4). These cucurbitacins were evaluated for their inhibitory effects on the growth of human colon (HCT-116), breast (MCF-7), lung (NCI-H460), and central nervous system (CNS) (SF-268) cancer cell lines, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes and on lipid peroxidation. Inhibitory activities of cucurbitacins B (1), D (2), E (3) and I (4), respectively, were for colon 81.5, 80.4, 77, and 65% at 0.4 microM, breast 87, 78, 66.5, and 12% at 0.4 microM, lung 96, 43, 37 and 2% at 0.1 microM and CNS 92, 25, 24 and 4% at 0.05 microM. Adriamycin (doxorubicin) was used as a positive control, which showed 64, 47, 45 and 71% inhibition of HCT-116 (colon), MCF-7 (breast), NCI-H460 (lung) and SF-268 (CNS) cell lines, respectively, at 0.3 x 10(-5) M. Compounds 1, 2, 3, and 4 inhibited the COX-2 enzyme by 32, 29, 35, and 27%, respectively, at 100 microg/ml. However these compounds did not inhibit the COX-1 enzyme at this concentration. Ibuprofen, naproxen and vioxx, commercial antiinflammatory drugs, were tested as controls for the inhibition of COX-1 and COX-2 enzymes at concentrations of 2.1, 2.5 and 1.67 microg/ml, respectively. Ibuprofen and naproxen exhibited 59 and 95% COX-1, and 53 and 79% COX-2 inhibitory activities, respectively. Vioxx showed specific COX-2 inhibition by 71%. Also, cucurbitacins 1 and 4 inhibited lipid peroxidation by 59 and 23%, respectively, at 100 microg/ml.

Anti-Inflammatory Agents↗
PubMed2001

Consumption of residue containing cucurbitacin feeding stimulant and reduced rates of carbaryl insecticide by western corn rootworm (Coleoptera: Chrysomelidae).

Application of insecticide at a reduced rate with a cucurbitacin-based feeding stimulant is a viable alternative to a broadcast insecticide application for control of adult western corn rootworms, Diabrotica virgifera virgifera, LeConte. Because of the small amount of material applied, it is conceivable that a high density of beetles could consume all of the spray residue before economic control is achieved. A laboratory experiment was conducted to determine the amount of cucurbitacin-based spray residue consumed by beetles. Dried residue of four treatments were exposed to three groups of 10 rootworm beetles for 1 h each. Treatments consisted of a cucurbitacin-based adjuvant (Cidetrak CRW, Trécé, Salinas, CA) with carbaryl insecticide (Sevin XLR Plus, Rhone Poulenc, Research Triangle Park, NC) mixed at 0, 0.12, 1.2, and 12 g (AI)/liter. For the treatment with cucurbitacin adjuvant only (no insecticide), beetles consumed 0.029 mg beetle(-1) h(-1) of exposure. Approximately 54% of the beetles were recorded as feeding at any given time during the 60-min feeding period. However, when the spray residue contained carbaryl, no weight loss of treatment residue was measured, though the beetles were observed to feed from the residue during the first few minutes of exposure. When residue included insecticide, beetles quickly ceased feeding (within 20 min), and toxicity behavior was observed 30 min after initial exposure for up to 75% of the beetles, which were classified as moribund (unable to stand upright). Beetle mortality was recorded 24 h after exposure and demonstrated that male beetles (53% dead for three insecticide treatments) were more susceptible to carbaryl toxicity than female beetles (28% dead for three insecticide treatments). Regression analysis showed a significant positive relationship between mortality of female beetles and ovarian development. Based on the measurements of this experiment, it is unlikely that realistic beetle densities would consume enough spray residue to prevent economic control of the beetle population.

Animals↗
PubMed1989

New cucurbitacin glycosides from Picrorhiza kurrooa.

From the roots of Picrorhiza kurrooa Royle and Benth., seven cucurbitacin glycosides have been isolated and structurally elucidated mainly by NMR and mass spectroscopy. Four of them (4, 5, 6, 7) are new and two, the 2-O-glycoside of cucurbitacin B (25-acetoxy-2-beta-glucosyloxy-16,20-dihydroxy-9-methyl-19-norl anosta-5, 23-diene-3,11,22-trione) and the 2-O-glucoside of 23,24 didydrocucurbitacin B (25-acetoxy-2-beta-glucosyloxy-16,20-dihydroxy-9-methyl-19-norl anost-5-ene-3, 11-22-trione) were so far not reported as constituents of this plant. The four new cucurbitacins could be identified as 2-beta-glucosyloxy-3,16,20,25-tetrahydroxy-9-methyl-19-norlanos ta-5, 23-diene-22-one, 2-beta-glucosyloxy-3,16,20,25-tetrahydroxy-9-methyl-19-norlanos t-5-ene-22-one, the 2-O-glucoside of cucurbitacin Q (25-acetoxy-2-beta-glucosyloxy-3,16,20-trihydroxy-9-methyl-19-n orlanosta-5, 23-diene-11,22-dione), and the 2-O-glucoside of deacetoxycucurbitacin B (2-beta-glucosyloxy-16,20-dihydroxy-9-methyl-19-norlanosta-5 , 24-diene-3,11,22-trione).

Animals↗
PubMed1996

Effect of cucurbitacins on mRNA coding for laccase in Botrytis cinerea.

The effect of cucurbitacin and of Ecballium extract on the formation of mRNA coding for laccase was examined in cultures of Botrytis cinerea grown with inducers of laccase formation, in the presence or absence of the inhibitory compounds. RNA was isolated from the cultures and probed with specific DNA probes for laccase. As an internal control, the RNA was probed for Botrytis beta-tubulin mRNA. From an analysis of the results it is clear that cucurbitacin I and Ecballium extract specifically repress the amount of mRNA coding for laccase. This could account for the previously observed repression of laccase formation by cucurbitacins.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Ellagic acid derivatives and cytotoxic cucurbitacins from Elaeocarpus mastersii.

Bioassay-guided investigation of the bark of Elaeocarpus mastersii using KB (human oral epidermoid carcinoma) cells as a monitor led to the isolation of two cucurbitacins, cucurbitacin D and cucurbitacin F as cytotoxic principles, together with two ellagic acid derivatives, 4'-O-methylellagic acid 3-(2",3"-di-O-acetyl)-alpha-L-rhamnoside (1) and 4,4'-O-dimethylellagic acid 3-(2",3"-di-O-acetyl)-alpha-L-rhamnoside (2). These compounds were evaluated against a panel of human tumor cell lines.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Ecballium elaterium: an in vitro source of cucurbitacins.

Biomass and secondary metabolite accumulation were assayed on a wide range of auxins, cytokinins and their combinations using Ecballium elaterium callus tissue. The best combination was that consisting of alpha-naphthalene acetic acid (NAA) and benzylamino purine (BAP) (1 mg/l of medium, each). NAA and BAP were set up in a grid to determine concentrations that produced the best callus as regards fresh and dry weights and yield of cucurbitacins, particularly cucurbitacin E. The best combination for callus proliferation consisted of 5 mg/l NAA and 5 mg/l BAP, reaching a peak at week 5. For cucurbitacin production, an optimum yield was obtained at week 3 with 5 mg/l NAA.

Cells, Cultured↗
PubMed1994

Cucurbitacins: differential cytotoxicity, dereplication and first isolation from Gonystylus keithii.

A characteristic pattern of differential cytotoxicity of extracts of Iberis amara seeds, predominantly toward renal tumor, brain tumor, and melanoma cell lines in the NCI human disease-oriented tumor screening panel, was traced to cucurbitacins E [1] and I [2]. This same differential cytotoxicity profile was detected in extracts of Begonia plebeja and Gonystylus keithii. Computer-assisted recognition of these profiles was followed by a rapid chemical fractionation, thus permitting the efficient dereplication of those extracts containing cucurbitacins B [3] and D [4], respectively. This is the first report of cucurbitacins from the genus Gonystylus.

Antineoplastic Agents, Phytogenic↗
PubMed1994

Cucurbitacins, cell adhesion inhibitors from Conobea scoparioides.

In the course of screening natural products for antagonists of CD18-mediated cell adhesion, an extract with inhibitory activity was identified from the stem and leaves of Conobea scoparioides. Bioassay-guided fractionation led to a pure compound, identified by spectroscopy as cucurbitacin E [1]. Although many biological activities have been reported for the cucurbitacins, this is the first report of cell adhesion inhibition. Furthermore, closely related cucurbitacin analogues had different potencies, pointing to substructural features that are important for the activity.

Actins↗
PubMed1991

Cucurbitacin contents in Hemsleya dolichocarpa.

Hemsleya dolichocarpa was studied for its cucurbitacin contents during growing period. A colorimetric method was used to determine the total cucurbitacin levels, and a TLC densitometric assay was employed for estimating dihydrocucurbitacin F and its acetate, two active principles in Hemsleya plants. Cucurbitacin contents rise progressively from May to November; the month of November is thus the most desirable time for harvesting plant materials for medicinal uses. It was noticed that the spoiled plant samples gave an intense color reaction while dihydrocucurbitacin F and its acetate levels were not significantly altered. The accuracy of the assays is discussed.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Effect of cucurbitacin D on in vitro growth of Xenorhabdus and Photorhabdus spp., symbiotic bacteria of entomopathogenic nematodes.

In vitro assays were conducted to determine the effect of cucurbitacin D, an oxygenated tetracyclic triterpenoid found in cucurbits, on the growth of Xenorhabdus isolated from Steinernema carpocapsae (All, Mexican, Agriotos strains), Steinernema riobravis, Steinernema glaseri (NC strain, strain 27), and Photorhabdus from Heterorhabditis bacteriophora (NC, Lewiston strains), and Heterorhabditis sp. (FL2122 strain). Cucurbitacin D inhibited the growth of four isolates, had no effect on the growth of four isolates, and stimulated the growth of one isolate. Results are discussed in relation to progeny production of entomopathogenic nematodes from insects that have eaten plant material containing cucurbitacin D. This is the first report of an effect of a plant secondary compound on the bacterial symbionts of entomopathogenic nematodes.

Animals↗
PubMed2002

Cucurbitacins from Trichosanthes kirilowii as the inhibitory components on tyrosinase activity and melanin synthesis of B16/F10 melanoma cells.

Cucurbitacins 1 and 2 were isolated from the root of Trichosanthes kirilowii by tyrosinase inhibitory activity-guided fractionation. Spectroscopic analysis revealed that compounds 1 and 2 were cucurbitacin D and 23,24-dihydro-cucurbitacin D, respectively. Compounds 1 and 2 effectively inhibited the activity of tyrosinase (IC(50) = 0.18 microM and 6.7 microM, respectively), and the synthesis of melanin (IC(50) = 0.16 microM and 7.5 microM, respectively) in B16/F10 melanoma cells.

Animals↗
PubMed1997

Anti-inflammatory and analgesic effects of cucurbitacins from Wilbrandia ebracteata.

The anti-inflammatory and antinociceptive actions of the CH2Cl2 extract and semipurified fraction (F-III) from roots of Wilbrandia ebracteata Cogn. have been investigated in rats and mice. The CH2Cl2 extract (1-10 mg/kg, i.p.; ID50 5 mg/kg) and (3-30 mg/kg, p.o.; ID50 15 mg/kg) inhibited, in a dose-related manner, carrageenan-induced paw edema in rats. The subfraction (F-III) from CH2Cl2 extract and compounds isolated as cucurbitacin B and E also inhibited carrageenan-induced edema. The CH2Cl2 extract and F-III also exhibited significant analgesic action in acetic acid-induced pain in mice. In the formalin test, the CH2Cl2 extract (0.3-10 mg/kg, i.p.) and (3-30 mg/kg, p.o.) caused inhibition of the neurogenic (first phase) and inflammatory phase (second phase) of formalin-induced pain. However, the CH2Cl2 extract was more effective in relation to the second phase than in inhibition of the formalin-induced edema. These findings suggest that CH2Cl2 extract has potent anti-inflammatory and analgesic action and that F-III and cucurbitacin B and E may account for these actions.

Analgesics↗