Literatura académica sobre el tema "Costunolido"

Saussurea lappaClarke (SLC) has been used as a traditional medicine in Korea, China, and Japan for the treatment of abdominal pain and tenesmus. Costunolide, a sesquiterpene lactone isolated from SLC, has diverse medicinal effects. However, the anticancer effects of costunolide are still unclear in breast cancer. In this study, we demonstrate that costunolide suppresses tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNFα-induced NF-κB activation. Costunolide inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in thein vivomouse orthotopic tumor growth assays. In addition, costunolide inhibitedin vitroTNFα-induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNFα-induced NF-κB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-κB-dependent gene to mediate breast cancer cell growth and metastases. Therefore, we conclude that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNFα-induced NF-κB activation, suggesting that costunolide as well as SLC may be promising anticancer drugs, especially for metastatic breast cancer.

Costunolide is a naturally occurring sesquiterpene lactone that demonstrates various therapeutic actions such as anti-oxidative, anti-inflammatory, and anti-cancer properties. Costunolide has recently emerged as a potential anti-cancer agent in various types of cancer, including colon, lung, and breast cancer. However, its mode of action in skin cancer remains unclear. To determine the anti-cancer potential of costunolide in skin cancer, human epidermoid carcinoma cell line A431 was treated with costunolide. A lactate dehydrogenase assay showed that costunolide diminished the viability of A431 cells. Apoptotic cells were detected by annexin V/propidium iodide double staining and Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay assay, and costunolide induced cell apoptosis via activation of caspase-3 as well as induction of poly-ADP ribose polymerase cleavage in A431 cells. In addition, costunolide elevated the level of the pro-apoptotic protein Bax while lowering the levels of anti-apoptotic proteins, including Bcl-2 and Bcl-xL. To address the inhibitory effect of costunolide on cell proliferation and survival, various signaling pathways, including mitogen-activated protein kinases, signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NF-κB), and Akt, were investigated. Costunolide activated the p38 and c-Jun N-terminal kinase pathways while suppressing the extracellular signal-regulated kinase (ERK), STAT3, NF-κB, and Akt pathways in A431 cells. Consequently, it was inferred that costunolide suppresses cell proliferation and survival via these signaling pathways. Taken together, our data clearly indicated that costunolide exerts anti-cancer activity in A431 cells by suppressing cell growth via inhibition of proliferation and promotion of apoptosis. Therefore, it may be employed as a potentially tumor-specific candidate in skin cancer treatment.

Abstract Costunolide, a natural sesquiterpene lactone, has multiple pharmacological activities such as neuroprotection or induction of apoptosis and eryptosis. However, the effects of costunolide on pro-survival factors and enzymes in human erythrocytes, e.g. glutathione and glucose-6-phosphate dehydrogenase (G6PDH) respectively, have not been studied yet. Our aim was to determine the mechanisms underlying costunolide-induced eryptosis and to reverse this process. Phosphatidylserine exposure was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry, and intracellular glutathione [GSH]i from high performance liquid chromatography. The oxidized status of intracellular glutathione and enzyme activities were measured by spectrophotometry. Treatment of erythrocytes with costunolide dose-dependently enhanced the percentage of annexin-V-binding cells, decreased the cell volume, depleted [GSH]i and completely inhibited G6PDH activity. The effects of costunolide on annexin-V-binding and cell volume were significantly reversed by pre-treatment of erythrocytes with the specific PKC-α inhibitor chelerythrine. The latter, however, had no effect on costunolide-induced GSH depletion. Costunolide induces eryptosis, depletes [GSH]i and inactivates G6PDH activity. Furthermore, our study reveals an inhibitory effect of chelerythrine on costunolide-induced eryptosis, indicating a relationship between costunolide and PKC-α. In addition, chelerythrine acts independently of the GSH depletion. Understanding the mechanisms of G6PDH inhibition accompanied by GSH depletion should be useful for development of anti-malarial therapeutic strategies or for synthetic lethality-based approaches to escalate oxidative stress in cancer cells for their sensitization to chemotherapy and radiotherapy.

Bioactivity-directed isolation work on the New Zealand liverwort Hepatostolonophora paucistipula afforded the sesquiterpene lactones (-)- ent-costunolide (1) and (-)- ent-arbusculin B (2) as cytotoxic compounds. This is the first report of 1, enantiomeric to the known germacranolide (+)-costunolide (3).

Background/Aims: The sesquiterpene lactone Costunolide is effective against various disorders including inflammation and malignancy. The substance is effective in part by triggering suicidal death or apoptosis of tumor cells. Mechanisms involved include altered function of transcription factors and mitochondria. Erythrocytes lack nuclei and mitochondria but are – in analogy to apoptosis of nucleated cells – able to enter suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether Costunolide induces eryptosis and, if so, to shed light on the mechanisms involved. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) formation from 2’,7’-dichlorodihydrofluorescein (DCF)-dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to Costunolide (15 µg/ml) significantly enhanced the percentage of annexin-V-binding cells, significantly decreased forward scatter and significantly increased Fluo3-fluorescence, DCF-fluorescence, and ceramide abundance. The effect of Costunolide on annexin-V-binding was significantly blunted by removal of extracellular Ca2+. Conclusion: Costunolide triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry and paralleled by oxidative stress and ceramide formation.

Abstract(±)-epi-Costunolide has been synthesized through a seven-step procedure starting from (E,E)-farnesol. The key step includes an intramolecular allylation of an aldehyde through a chromium(II)-mediated Nozaki–Hiyama–Kishi reaction, in which more than one equivalent of CrCl2 has been recognized as the most effective reagent to promote the conversion. An anti-inflammatory screen showed that epi-costunolide is a moderate inhibitor of B lymphocyte proliferation.

Sesquiterpene lactones constitute a major class of bioactive natural products. One of the naturally occurring sesquiterpene lactones is costunolide, which has been extensively investigated for a wide range of biological activities. Multiple lines of preclinical studies have reported that the compound possesses antioxidative, anti-inflammatory, antiallergic, bone remodeling, neuroprotective, hair growth promoting, anticancer, and antidiabetic properties. Many of these bioactivities are supported by mechanistic details, such as the modulation of various intracellular signaling pathways involved in precipitating tissue inflammation, tumor growth and progression, bone loss, and neurodegeneration. The key molecular targets of costunolide include, but are not limited to, intracellular kinases, such as mitogen-activated protein kinases, Akt kinase, telomerase, cyclins and cyclin-dependent kinases, and redox-regulated transcription factors, such as nuclear factor-kappaB, signal transducer and activator of transcription, activator protein-1. The compound also diminished the production and/expression of proinflammatory mediators, such as cyclooxygenase-2, inducible nitric oxide synthase, nitric oxide, prostaglandins, and cytokines. This review provides an overview of the therapeutic potential of costunolide in the management of various diseases and their underlying mechanisms.

Costunolide (COS), a natural sesquiterpene lactone originally isolated from Inula helenium (Compositae), shows potent neuroprotective effects against oxidative stress-mediated injuries of PC12 cells via activating transcription factor Nrf2.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Cosmos sulphureus Cav. é uma espécie que foi introduzida no Brasil como ornamental e hoje se comporta como uma planta daninha, apresentando elevado poder invasivo no ambiente, devido ao seu potencial alelopático, suprimindo inclusive o crescimento de outras plantas daninhas. Essa característica da planta a torna uma potencial candidata para obtenção de herbicidas naturais, os aleloquímicos, que uma vez isolados e caracterizados poderão ser utilizados diretamente como tal ou então para a semi-síntese de novos compostos. Em vista disso, objetivou-se avaliar e caracterizar o potencial alelopático de C. sulphureus e, também, extrair, fracionar e isolar os aleloquímicos promotores do efeito alelopático. Caracterizou-se o potencial alelopático de C. sulphureus pelo método de liberação por decomposição e por exsudação radicular (planta “in vivo”). A decomposição de plantas de C. sulphureus resultou em efeito alelopático inibitório sobre Lactuca sativa, Amaranthus viridis e Panicum maximum, principalmente na incorporação da maior quantidade de material vegetal.Exsudatos radiculares de C. sulphureus resultaram em efeito alelopático inibitório sobre A. viridis e P. maximum. Dentre os dois modos de liberação de aleloquímicos por C. sulphureus estudados, a exsudação radicular foi o mais ativo (planta “in vivo”). Também foi realizada a extração de folhas de C. sulphureus com água e solventes orgânicos e verificou-se a cito/fitotoxicidade dos extratos. Os extratos mais ativos foram fracionados utilizandose de técnicas de cromatografia e as frações obtidas foram testadas por meio de bioensaios (isolamento biodirigido). As frações bioativas foram analisadas para identificação das substâncias presentes por meio de HPLC-UV-MS e ressonância magnética nuclear. O extrato diclorometânico de folhas e o acetônico de raízes proporcionaram inibição significativa no alongamento de coleóptilos de trigo, e o primeiro apresentou-se mais fitotóxico às espécies receptoras (Allium cepa, L. sativa, Lepidium sativum, Lycopersicum esculentum, A. viridis, Echinochloa crus-galli, Panicum maximum e Urochloa decumbens). Foram isolados quinze compostos das folhas e cinco de raízes. Todos os compostos isolados das raízes, com exceção ao estigmasterol são fenilpropanóides, e foram isolados pela primeira vez na espécie C. sulphureus. Os compostos álcool 1’,2’-epoxi-3’,4-di-O-isobutiril-Z-coniferil e álcool 1',2'-dihidroxi-3',4-di-O-isobutirilconiferil, isolados das raízes, descrevem-se pela primeira vez na literatura. Os compostos majoritários isolados das folhas são lactonas sesquiterpênicas: costunolido, reinosina e santamarina. Os três compostos se descrevem pela primeira vez na planta C. sulphureus, com exceção do costunolido que já foi isolado anteriormente nesta planta. Santamarina e costunolido foram os mais ativos, seguidos por reinosina. Amaranthus viridis e P. maximum foram as espécies mais sensíveis à ação das lactonas. As lactonas sesquiterpênicas isoladas das folhas são uma fonte potencial para modelos de novos tipos estruturais de herbicidas.
Cosmos sulphurous Cav. was introduced in Brazil as an ornamental plant and has become a problematic weed. This plant grows rapidly and it’s a dominant species, probably due to its allelopathic activity, suppressing the growth of other weeds. This characteristic makes C. sulphureus a potential source of natural herbicides (allelochemicals). When isolated and characterized they can be directly used as such or used to synthesize new related compounds. The aim of this study was to evaluate and characterize the allelopathic potential of C. sulphureus and to extract, fractionate and isolate the allelochemical promoters of the allelopathic effect. The allelopathic potential of C. sulphureus was characterized by the decomposition release method and by root exudation (“in vivo” plant). The decomposition of C. sulphureus resulted in allelopathic inhibitory effect on Lactuca sativa, Amaranthus viridis and Panicum maximum, mainly in the incorporation of the greater amount of plant material. Root extracts of C. sulphureus resulted in allelopathic inhibitory effect on A. viridis and P. maximum. Based on the results of this work, the main release pathway presented by C. sulphureus is root exudation ("in vivo" plant). Extraction of C. sulphureus leaves with water and organic solvents was also performed and the cytotoxicity of the extracts was checked. The most active extracts were fractionated using appropriate chromatography techniques and the fractions were tested by means of bioassays (biodirigid isolation). Bioactive fractions were analyzed in order to identify substances through HPLC-UV-MS and nuclear magnetic resonance (NMR). Dichloromethane extract of leaves and acetone extract of roots showed significant inhibition in wheat coleoptile elongation, and the first one was more phytotoxic to the target species (Allium cepa, L. sativa, Lepidium sativum, Lycopersicum esculentum, A. viridis, Echinochloa crus-galli, P. maximum and Urochloa decumbens). Fifteen compounds were isolated from leaves and five from roots. All compounds isolated from roots, except stigmasterol, are phenylpropanoids and were first isolated in C. sulphureus. The compounds 1’,2’-Epoxy-3’,4-di-Oisobutyryl-Z-coniferyl alcohol and 1',2'-Dihydroxy-3',4-di-O-isobutyrylconiferyl alcohol, isolated from roots, have never been described in the literature before. The major compounds isolated from leaves are sesquiterpene lactones: costunolide, reynosin and santamarin. The three major components of leaves are described for the first time to C. sulphureus, except costunolide, which was isolated from this plant before. Santamarin and costunolide were the most active compounds followed by reynosin. Amaranthus viridis and P. maximum were the most sensitive species to the action of the lactones. Sesquiterpene lactones isolated from leaves are a potential source for new herbicide structural models.
FAPESP: 2013/27140-7

博士
國立陽明大學
傳統醫藥研究所
101
Hepatocellular carcinoma (HCC) is a disease with dismal prognosis. Since the symptom and sign in early stage of HCC is not obvious, most patients are diagnosed at advanced stages with a limited chance for curative intention therapy. Besides, most HCC patients also have advanced fibrosis or cirrhotic changes on the normal liver counterpart. The difficulty in treatment of advanced HCC depends not only on the tumor-related factor, but also on the patient-related factor. To improve the therapeutic efficacy and toxicity for HCC, the development of radiosensitizers to decline needed RT dose in in-field tumor control and enhance out-field effect are critical issues in clinical practice. In the first part of study, the mitosis-arresting effect and radiosensitizing activity of costunolide, a sesquiterpene lactone isolated from Michelia compressa, on human HCC cells was examined. The result showed that costunolide reduced the viability of HA22T/VGH cells. It also caused a rapid G2/M arrest at 4 hours shown by DNA histogram. The increase in phosphorylated histone H3 (Ser 10)-positive cells and mitotic index indicates costunolide-treated cells are arrested at mitosis, not G2, phase. Immunofluorescence of alpha-tubulin for spindle formation further demonstrated these cells are halted at metaphase. Costunolide up-regulated the expression of phosphorylated Chk2 (Thr 68), phosphorylated Cdc25c (Ser 216), phosphorylated Cdk1 (Tyr 15) and cyclin B1 in HA22T/VGH cells. At optimal condition causing mitotic arrest, costunolide sensitized HA22T/VGH HCC cells to ionizing radiation with sensitizer enhancement ratio up to 1.9. It suggests that costunolide could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosis-arresting activity for cancer therapeutics further demonstrated that costunolide enhanced the killing effect of radiotherapy against human HCC cells. Doxorubicin is the most active single agent for chemotherapy of HCC with toxicity to heart and remaining normal liver. Drug formulation techniques, such as pegylation for liposomal nanoparticle, have been proven effective in reducing toxicity without compromising the therapeutic efficacy. However, the variety in constitutions of liposomes may cause different toxicity profile, especially to the monocyte/macrophage lineage. Since macrophages of mononuclear phagocytes system are pivotal in determining pegylated liposomal doxorubicin (PLD) nanoparticles clearance, in vitro model using macropahges was used to test the drug uptake, retention, function and cytotoxicity. This in vitro model could be extended to evaluate the normal tissue complication probability for HCC therapy. In the second part of study, two PLD nanoparticles were used in this study. The major difference between PLD-D and PLD-H is that their phospholipid bilayers are composed of distearoyl phosphatidylcholine (DSPC) and hydrogenated soybean phosphatidylcholine (HSPC), respectively. Human CD14+ monocytes were isolated from peripheral blood to prepare macrophages. The results showed that the uptake of PLD-H was rapidly detected at 10 min and kept increasing to 4 h followed by a decline thereafter, whereas that of PLD-D had similar profile with much less doxorubicin fluorescence detected, indicating a greater amount of doxorubicin retention of PLD-H. PLD-H, at higher concentration, decreased the viability and impaired cell membrane integrity of macrophages with an extent greater than PLD-D. The morphological observation showed a more extensive necrosis in PLD-H-treated macrophages. The phagocytosis function of macrophage was inhibited with a greater extent in PLD-H-treated macrophages. The PLD containing HSPC may cause retention of doxorubicin with greater amount and longer period in human macrophages than that containing DSPC. This effect was accompanied by greater toxicity and more profound dysfunction. The correlation of this differential effect to clinical outcome remains to be extensively investigated by performing in vivo experiments or conducting clinical trials. Furthermore, this ex vivo model may be a candidate platform for evaluating injury of normal tissues by liposomal nanoparticles in HCC treatment in the future.

碩士
國立高雄大學
生命科學系碩士班
104
Saussurea costus belonging a species of thistle in the genus Saussurea of the family Asteraceae is a perennial herb. It has been proved to possess numerous pharmaceutical ingredients. Sesquiterpene lactones were reported as major phyto constituents of this species. In order to search bioactive and novel metabolites, it resulted in the isolation of 17 compounds, including one novel sesquiterpenoid, saucostunoid C (3), four new sesquiterpenoids, saucostunoids A、B、D、E (1、2、4、5), and 12 known compounds, dehydrocostuslactone (6), costunolide (7), terpenoids-L (8),1-methyl-7-ethylnaphthalene (9), arbusculin E methyl ester (10), 11-acetoxy-4α-hydroxy-4β-methyldiydrocostol (11), 4α-hydroxy-4β-methyl-diydrocostol (12), cyperusol C (13), deacylcynaropicrin (14), cynarpicin (15), critonilide 4 (16), and lβ,4α-dihydroxy-5α,llβ-H-eudesman-6β,12-olide (17), from the crude extract of S. costus. The structures of these metabolites were determined by their spectroscopic analyses and comparison of the physical and spectroscopic data with those of the related known compounds. The anti-inflammatory activities of these obtained compounds were measured in vitro. At a concentration of 10 μM, compounds 2–8、10–12 and 17 reduced the levels of inducible nitric oxide synthase (iNOS). However, all obtained compounds did not affect cyclooxygenase-2 (COX-2). Compounds 8–10 exhibited in vitro weak cytotoxicity against MCF-7. Compounds 3 and 11–14 showed in vitro unremarkable hypoglycemic effect. It is noteworthy to mention that the polymerization occurred during rotary evaporation of costunolide (7) in the chromatographic process. The polymeric colloid was dissolved in appropriate amount of sulfate, then a certain amount methanol was added to the above solution to yield 8 and 9. The products can be used to verify that it's monomer is indeed costunolide (7). The polymeric colloid was further confirmed through thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and gel-permeation cleanup (GPC) methods.

Os objectivos deste trabalho consistiram em desenvolver um método de separação eficaz e reprodutível de modo a isolar as lactonas sesquiterpénicas - dehidrocostus e costunolida - de extractos do fungo parasita da espécie Laurus novocanariensis - Laurobasidium lauri; em testar os compostos relativamente às suas capacidades antioxidantes e bioactivas - citotoxicidade e alelopatia - e em obter uma quantidade considerável destas lactonas de modo a enviar para laboratórios em parceria para realização de testes de actividade anticancerígena in vitro (Instituto Canário de Investigação em Cancro), de antituberculose in vivo (Instituto politécnico Nacional, México), de actividade anti-inflamatória in vivo (UNIVALI, Brasil) e de actividade anti-ulcerativa in vivo. Neste trabalho foi possível isolar 116 mg de lactona costunolida com 97% de pureza através do fraccionamento do extracto de Madre de Louro em hexano pela técnica de cromatografia em coluna aberta com sistema de eluentes Hexano:Acetato de etilo (50:0 – 43:7 mL), procedendo à sua identificação por HPLC-MS e RMN 13C, não tendo sido possível atingir o mesmo objectivo para a lactona dehidrocostus. O extracto de Madre de Louro em Metanol demonstrou ser a amostra com maior poder antioxidante relativamente aos teste de ABTS, DPPH e FRAP, enquanto o extracto em Diclorometano apresentou maior poder antioxidante no teste do β-caroteno/ácido linoléico. No que toca aos ensaios biológicos, o extracto de madre de louro em hexano foi o que apresentou um valor de DL50 mais baixo (0,1mg/mL) representando assim maior poder de toxicidade perante as larvas de camarão (Artemia salina).
Universidade da Madeira