Search

Background: Kaurane-type diterpenoids, obtained from various natural sources, have shown many biological activities, including anti-inflammatory and antitumor effects. Caracasine, an ent -kaurane diterpenoid isolated from the flowers of Croton micans , was shown to induce apoptosis in leukaemia cell lines., Objective: The present study aimed to ascertain the compound's mechanism of cell death induction using two leukaemia cell lines, Jurkat E6.1 (T cell) and HL-60 (promyeloblast cells)., Methods: Cell death in Jurkat and HL60 cells were evaluated by flow cytometry for apoptosis with annexin-V/PI, mitochondrial membrane potential disturbance, changes in cell cycle, CD95 expression, caspase activation, Nuclear Factor kappa B inhibition, and differentiation into a neutrophil-like cell (dHL60)., Results: Caracasine (10 μM) increased the G0/G1 phase in Jurkat and arrested the cell cycle in the S phase in HL60. Caracasine increased CD95 expression ( p <0.01 in Jurkat and p <0.05 in HL60) and caspase-8 activation ( p <0.001 in Jurkat and p<0.05 in HL60). Caspase-9 was activated in both cell lines ( p <0.001) along with the decline in mitochondrial Δψm ( p <0.05 in Jurkat and p<0.001 in HL60). In HL60 cells, the kaurane induced neutrophil differentiation was assessed by CD40 expression and reactive oxygen species production. In Jurkat cells, caracasine inhibited the NF-κB pathway in cells pretreated with PHA to activate the NF-κB pathway, suggesting a possible role in inflammatory diseases., Conclusion: Caracasine induced apoptosis through the intrinsic and extrinsic pathways in both cell lines were evaluated which could be the leading structure for new anti-leukemic and anti-inflammatory drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Caracasine acid (CA) is an ent-3,4-seco-kaurene isolated from the plant Croton micans. Decreased cancer cell lines viability was reported upon CA treatment. The present study aimed to investigate the mechanism of CA induced cytotoxicity using two human cell lines, Jurkat E6.1 (human cell T lymphoma) and HL-60 (human acute promyelocytic leukemia). Significant increases of apoptotic cell death markers upon CA treatment were observed: annexin-V positiveness, potential mitochondrial disturbances, cell cycle changes, caspase activation, and CD95 expression. These effects were not detected in normal lymphocytes. CA induced the appearance of Bax, cleaved caspase 3, and cytochrome c release in Jurkat cells, and cleaved caspase 3 and phosphorylated p53 in HL60 cells. Likewise, downregulation of anti-apoptotic proteins such as Bcl-x (Jurkat), Bcl-2, and XIAP (HL60) was observed with CA treatment. Both pathways, intrinsic and extrinsic were activated when cell lines were treated with CA. NF-κB p65 inhibition was observed in Jurkat cells and cell differentiation in HL-60 cells. CA could be a potential leader compound for the development of new drugs for leukemia treatment in humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The galactan system biosynthesized by the red seaweed Gymnogongrus tenuis (Phyllophoraceae) is constituted by major amounts of κ/ι-carrageenans, with predominance of ι-structures, which were isolated by extraction with hot water in high yield (∼ 45%). A small amount of non-cyclized carrageenans mostly of the ν-type was also obtained. Besides, 12% of these galactans are agaran structures, which were present in major quantities in the room temperature water extracts, but they were also found in the hot water extract. They are constituted by 3-linked β-D-galactose units partially substituted on C-6 with sulfate or single stubs of β-D-xylose and 4-linked residues that comprise α-L-galactose units partially sulfated or methoxylated on C-3 or sulfated on C-3 and C-6 and 3,6-anhydro-α-L-galactose. Related structural patterns were previously found for agarans synthesized by other carrageenophytes. Results presented here show that these agarans are low molecular weight molecules independent of the carrageenan structures, with strong interactions between them., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of caracasine acid (1) derivatives were synthesized and evaluated for their in vitro cytotoxicity on human cancer-derived cell lines MCF-7 and PC-3, as well as for other activities such as antibacterial, antileishmanial and antitrypanosomal activity. Compound 1 was more effective than any of its derivatives against tested human cancer cell lines. PC-3 cells were more sensitive than MCF-7 to all compounds, particularly the methyl ester (2), the amide (9) and the epoxide (10). The evaluation of antiparasitic activity revealed that ester derivatives (2-8) and the amide derivative (9) were the most effective antileishmanial and antitrypanosomal compounds, even though their effect on Trypanosoma cruzi was modest. Finally, compound 1 and the derivatives evidenced a broad spectrum of antibacterial activity, as assayed against Gram-positive and Gram-negative bacteria., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Sulfated and pyruvylated galactans were isolated from three tropical species of the Bryopsidales, Penicillus capitatus, Udotea flabellum, and Halimeda opuntia. They represent the only important sulfated polysaccharides present in the cell walls of these highly calcified seaweeds of the suborder Halimedineae. Their structural features were studied by chemical analyses and NMR spectroscopy. Their backbone comprises 3-, 6-, and 3,6-linkages, constituted by major amounts of 3-linked 4,6-O-(1'-carboxy)ethylidene-d-galactopyranose units in part sulfated on C-2. Sulfation on C-2 was not found in galactans from other seaweeds of this order. In addition, a complex sulfation pattern, comprising also 4-, 6-, and 4,6-disulfated galactose units was found. A fraction from P. capitatus, F1, showed a moderate anticoagulant activity, evaluated by general coagulation tests and also kinetics of fibrin formation was assayed. Besides, preliminary results suggest that one of the possible mechanisms involved is direct thrombin inhibition., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The water extracts from red seaweeds Laurencia obtusa and Laurencia filiformis comprise complex sulfated agarans. Those from L. obtusa have 3-linked β-d-galactose units in part sulfated on 2-position or methylated on 6-position, while the 4-linked units are mostly 3,6-anhydro-α-l-galactose and α-l-galactose 6-sulfate, some of the latter units are substituted with β-d-xylose on 3-position, precluding alkaline cyclization. The 3-linked β-d-galactose units of the agarans from L. filiformis are mostly sulfated on 2-position, but approximately half of these residues also carry the 4,6-O-(1-carboxyethylidene) group. The 4-linked 3,6-anhydro-α-l-galactose units are methylated or substituted in part with single stubs of β-d-xylose on 2-position. This is the first time that substitution with xylose of 3,6-anhydro-α-l-galactose is reported. Besides, α-l-galactose 2-sulfate carrying single stubs of β-d-xylose on 3-position was also detected. These galactans have some common structural characteristics with those of other species of this genus, but also others that are specific for these species., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Fisturalines are bromotyrosine compounds isolated from marine sponges. Previous studies have shown antineoplasic, antiviral and antibacterial effects in Vitro; however, the possible effects of these compounds in hematologic malignancies have not been assessed., Methods: In the present study, the antiproliferative and pro apoptotic effects of Fistularin-3 (F) and 11-Deoxyfistularin-3 (DF) were assessed using the MTT method and annexin V/propidium iodide by flow cytometry using the cell lines: Jurkat E6.1 and U937. In addition, the cell cycle was assessed by flow cytometry., Results: Inhibition of the proliferative response was concentration and time dependent. The IC50 of F was 7.39 and 8.10 µM for Jurkat E6.1 and U937 respectively. At 24 and 48 h, in the U937 cell line, but not in the Jurkat cell line, both compounds induced up to 35% annexin V increase. Necrosis was not observed in any case. Compound F induced, in both cell lines, a decrease in the number of cells in the S phase and increase in the G0/G1 phase. In the Jurkat cell line only, there was an increase in the number of cells in the G2/M phase. Compound DF was not as effective as F., Conclusions: F is more active than DF in repressing the cell cycle and inducing apoptosis. Both compounds are potentially useful in the development of new drugs to treat hematologic malignancies.

Purpose: In search for new drugs derived from natural products for the possible treatment of cancer, we studied the action of agelasine B, a compound purified from a marine sponge Agelas clathrodes., Methods: Agelasine B was purified from a marine sponge Agelas clathrodes and assayed for cytotoxicity by MTT on two human breast cancer cells (MCF-7 and SKBr3), on a prostate cancer cells (PC-3) and on human fibroblasts. Changes in the intracellular Ca(2+) concentrations were assessed with FURA 2 and by confocal microscopy. Determination of Ca(2+)-ATPase activity was followed by Pi measurements. Changes in the mitochondria electrochemical potential was followed with Rhodamine 123. Apoptosis and DNA fragmentation were determined by TUNEL experiments., Results: Upon agelasine B treatment, cell viability of both human breast cancer cell lines was one order of magnitude lower as compared with fibroblasts (IC(50) for MCF-7 = 2.99 μM; SKBr3: IC(50) = 3.22 μM vs. fibroblasts: IC(50) = 32.91 μM), while the IC(50) for PC-3 IC(50) = 6.86 μM. Agelasine B induced a large increase in the intracellular Ca(2+) concentration in MCF-7, SKBr3, and PC-3 cells. By the use of confocal microscopy coupled to a perfusion system, we could observe that this toxin releases Ca(2+) from the endoplasmic reticulum (ER). We also demonstrated that agelasine B produces a potent inhibition of the ER Ca(2+)-ATPase (SERCA), and that this compound induced the fragmentation of DNA. Accordingly, agelasine B reduced the expression of the anti-apoptotic protein Bcl-2 and was able to activate caspase 8, without affecting the activity of caspase 7., Conclusions: Agelasine B in MCF-7 cells induce the activation of apoptosis in response to a sustained increase in the [Ca(2+)]( i ) after blocking the SERCA activity. The reproduction of the effects of agelasine B on cell viability and on the [Ca(2+)]( I ) obtained on SKBr3 and PC-3 cancer cells strongly suggests the generality of the mechanism of action of this toxin.

From the stems of Croton micans Sw., five new 3,4-seco-ent-kaurene dimers: micansinoic acid (1), isomicansinoic acid (2), and the dimethyl (3), monomethyl (4) and monoethyl ester (5) of micansinoic acid were isolated. The structures of the new compounds were elucidated by spectroscopic data interpretation, mainly 1D and 2D NMR experiments and MS. These compounds are the first 3,4-seco-ent-kaurene dimers from a Croton species.

ent-Kauranes are diterpene-type compounds commonly found in most plant species, especially from the Euphorbiaceae family. These compounds have been studied due to their anti-inflammatory and anti-tumor properties. Regulation of apoptosis, or programmed cell death, is commonly bypassed by tumoral cells, giving rise to uncontrolled proliferating cells, which eventually become carcinogenic. In a previous work, we showed that both mRNA and protein expression levels of the antiapoptotic gene Bcl-2 are reduced in MCF-7 cancer cells by the effect of the natural diterpene ent-16β-17α-dihydroxykaurane (DHK). This effect was not directly associated with the inactivation of NF-κB, as has been shown with other diterpenes compounds. Herein, we report that DHK is dissociating the Ap2α-Rb activating complex, affecting its binding ability for the Bcl-2 gene promoter. These events down-regulate Bcl-2 and is temporally accompanied by the induction of E2F1 and its target pro-apoptotic gene Puma. Disruption of the Rb-Ap2α activation complex was corroborated by chromatin immunoprecipitation and protein immunolocalization, which also revealed that Ap2α sorts out from the nucleus and relocalizes in the cell periphery. Taken together, our study confirms the regulation of Bcl-2 gene transcription by the Ap2α-Rb complex and describes a singular protein relocalization for Ap2α induced by DHK, implicating a new potential therapeutic target to differentially onset apoptosis in tumor cells.

The essential oil from leaves of Croton gossypiifolius Vahl. (Euphorbiaceae) was obtained by hydrodistillation, and analyzed by GC/FID and GC/MS. The constituents were identified by their mass spectra and Kovats' indices. Fifty-one compounds accounting for 92% of the oil were detected, and 47 of them were identified. The oil was dominated by oxygenated sesquiterpenes with the major presence of alpha-cedrene oxide (18.6%), spathulenol (16.3%), valencene (5.8%), geranyl-pentanoate (5.3%), alpha-cadinol (4.0%), germacrene D (3.5%) and longifolene (3.3%).

In the course of searching for bioactive compounds from Croton species from Venezuela, two seco-entkaurenes isolated from flowers of Croton caracasana were evaluated in vitro for their effect on cell viability by the standard MTT assay in nine human cancer cell lines of different origins and one primary culture. Both compounds induced cytotoxicity in the range of 2 to 25 microM for caracasine and 0.8 to 12 microM for caracasine acid. However, for the normal fibroblasts and the cell lines, HeLa, MCF-7, PC-3, LoVo, X-17, Jurkat E6.1 and Jurkat JCaM1.6, the IC50 values of caracasine acid were lower than their counterparts. Interestingly, no differences in IC50 were recorded for the leukemic cell lines U937 and K562. It can be concluded that the acid moiety in the structure enhances the cytotoxic effect of caracasine by a pathway which seems not to be activated in the leukemic cell lines tested.

The aqueous extract of Croton cuneatus Klotz. (Euphorbiaceae), was tested for its antinociceptive effects using chemical and thermal test models in mice. Anti-inflammatory activity was determined in Sprague-Dawley rats in a model of acute plantar inflammation induced by bovine serum albumin. Croton cuneatus aqueous extract at doses of 7 mg/kg showed a significant anti-inflammatory effect compared with commonly used non-stereoidal drugs as ketoprofen, sodium diclofenac and ASA (acetylsalicylic acid).

A new isoflavone 5,7,4'-trihydroxy-3'-(3-hydroxy-3-methylbutyl)isoflavone (isowigtheone hydrate) (1), together with six known isoflavones 2-7 and (-)epicatechin, were isolated from the root barks of Brosimum utile. Their structures were established on the basis of spectroscopic evidence. The in vitro cytotoxic activity of the new compound 1 was evaluated against cell lines MCF7 (human breast carcinoma), PC3 (human prostate carcinoma), HT29 (human colon cancer) and human dermis fibroblasts.

Analysis of the dichloromethane extract of the aerial parts of Croton cuneatus led to the isolation of the new glutarimide alkaloids: julocrotol (1), isojulocrotol (2), and julocrotone (3) along with the known compounds julocrotonine (4), lichexanthone (5) and selin-11-en-4alpha-ol (6). The structures of the new compounds were established by spectral methods. The in vitro cytotoxic activity of Compounds 1-6 was evaluated against six human tumor cells lines.

Croton malambo (K.) bark aqueous extract, popularly known in Venezuela as "palomatias" or "torco" was tested for acute toxicity and for its anti-inflammatory and antinociceptive effects using tail flick and writhing syndrome tests models, respectively. Croton malambo aqueous extract (6.15 mg/kg i.p.) administered intraperitoneally had a significant antinociceptive and anti-inflammatory effects compared to acetylsalicylic acid (200mg/kg p.o.) and sodium diclofenac (5.64 mg/kg p.o.). Studies to determine correlation between chemical composition and pharmacological activity are underway.

Analysis of the ethyl acetate extract of the aerials parts of Podocalyx loranthoides led to the isolation of I 7, II 4'-dimethylamentoflavone (1) and II 4'-methylamentoflavone (2). Compound (1) gave a moderate effect against Leishmania mexicana promastigotes.

The isolation of multicaulisin, a new Diels-Alder type adduct from Morus multicaulis roots is reported.

11-Deoxyfistularin-3 (1), a new bromotyrosine derivative, was isolated among other known compounds such as fistularin-3 (2), aerothionin (3), and 11-oxoaerothionin (4) from the Caribbean sponge Aplysinafistularis (Aplysinellidae). The structure of 1 was determined by spectroscopic analysis and showed in vitro activity against the human breast carcinoma cell line MCF-7.

Illimaquinone, a sponge metabolite that disrupts the Golgi complex in mammalian cells, stopped proliferation and induced morphological and ultrastructural changes in promastigotes of L. mexicana. Radioactive labeling of proteins demonstrates an increased excretion function and diminution of membrane acid phosphatase activity, due probably to the vesiculation of the Golgi complex and alteration of the cell protein sorting mechanism. The result indicated that illimaquinone could be useful for the study of intracellular traffic in Trypanosomatidae.

The Palauan sponge Axinyssa aplysimoides contained (3S*,5R*,6R*,9R*)-3-isocyano-1(10)-cadinene[2],(3S*,5R*,6R*, 9R*)-3-formamido-1(10)-cadinene[3], and (E)-(4-hydroxystyryl)trimethylammonium chloride [6], together with the known diterpenes (-)-neoverrucosan-5beta-ol[4] and (+)-homoverrucosan-5beta-ol[5].