Activity Of Sesquiterpene Lactones Research Articles

Isoalantolactone suppresses gallbladder cancer progression via inhibiting the ERK signalling pathway

Context Gallbladder cancer (GBC) is the most common malignant tumour of the biliary tract. Isoalantolactone (IAL), an active sesquiterpene lactone compound isolated from the roots of Inula helenium L. (Asteraceae), has antitumour effects. Objective This study investigates the effects of IAL on GBC. Materials and methods In vitro, NOZ and GBC-SD cells were treated with IAL (0, 10, 20 and 40 μM) for 24 h. The DMSO-treated cells were selected as a control. Cell proliferation, migration, invasion and apoptosis were measured by the CCK-8 assay, transwell assay, flow cytometry and western blot. In vivo, subcutaneous tumour xenografts were constructed by injecting nude mice (BALB/C) with 5 × 106 NOZ cells. Mice were divided into the control group (equal amount of DMSO), the IAL group (10 mg/kg/day) and the IAL + Ro 67-7476 group (IAL, 10 mg/kg/day; Ro 67-7476, 4 mg/kg/day). The study duration was 30 days. Results Compared with the DMSO group, cell proliferation of NOZ (IC50 15.98 μM) and GBC-SD (IC50 20.22 μM) was inhibited by about 70% in the IAL 40 μM group. Migration and invasion were suppressed by about 80%. Cell apoptosis rate was increased about three-fold. The phosphorylation level of ERK was decreased to 30–35%. Tumour volume and weight (about 80% reduction) were suppressed by IAL in vivo. Moreover, the effects of IAL were abolished by Ro 67-7476 in vitro and in vivo. Discussion and conclusions Our findings indicate that IAL could inhibit GBC progression in vitro and in vivo by inhibiting the ERK signalling pathway.

Sesquiterpene Lactones from Vernonia tufnelliae: Structural Characterization and Biological Evaluation.

The genus Vernonia is an extremely rich source of biologically active sesquiterpene lactones. The present report describes the spectroscopic structure elucidation and the cytotoxic and antimicrobial properties of five hitherto unknown germacranolide-like sesquiterpenoids and several known compounds. These new derivatives include a compound (1) with an unprecedented 10/5/5/6 tetracyclic framework featuring a hexahydro-1H,3H,7H-furo[3',4':3,4]furo[3,2-c]pyridin-1-one core resulting from an intramolecular cyclization cascade involving a methacrylate substituent and a low molecular weight amine. Furthermore, an elemane-germacranolide hybrid (2) and three amino acid-derived lactones (3-5) were characterized. A plausible biosynthetic pathway to the key alkaloid is presented, while shielding tensor calculations using DFT in combination with the DP4+ method were applied to elucidate its stereostructure. The newly characterized compounds along with ten known sesquiterpene lactones and phenolic compounds have been isolated from Vernonia tufnelliae, a medicinal plant from the western region of Cameroon. Their structures were consistent with spectroscopic and spectrometric data recorded. The present report is the first investigation of the chemistry and biology of V. tufnelliae.

Xanthatin inhibits non-small cell lung cancer proliferation by breaking the redox balance.

Lung cancer is the cancer with the highest mortality, and non-small cell lung cancer (NSCLC) accounts for more than 80%. Tumor cells often have high reactive oxygen species (ROS) and antioxidant capacity. Redox balance is very important for tumor. The decline of antioxidant capacity and excessive ROS will induce the death of tumor cells. Destroying the redox balance of tumor cells is a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. We observed that xanthatin induced the up regulation of mitochondrial ROS and mitochondrial damage. Meanwhile, our results showed that xanthatin could inhibit system xc - and reduce glutathione (GSH) synthesis. Antioxidant GSH and N-acetyl- l-cysteine (NAC) significantly reversed cell proliferation inhibition and apoptosis induced by xanthatin. β-Mercaptoethanol (β-ME) which can avoid inhibition of systemxc - can also reverse the inhibition of cell proliferation induced by xanthatin, si-SLC7A11 was the opposite. Based on these results, we believe that the inhibition of xanthatin on the proliferation of NSCLC cells may be related to breaking the intracellular redox balance. Our data suggest that xanthatin is a promising antitumor candidate for the treatment of NSCLC.

Chartolepis intermedia Boiss. and Centaurea ruthenica Lam. – New Medicina Plants Containing Pharmacologically Active Compounds

BACKGROUND: Chartolepis intermedia Boiss. and Centaurea ruthenica Lam. are new medicinal plants containing pharmacologically active sesquiterpene lactones grossheimin and cynaropicrin. The article discusses the methods for the isolation of grossheimin and cynaropicrin and presents the results of studying the pharmacological activity of the isolated sesquiterpene lactones. AIM: The aim of this work was chemical, morphological, and anatomical study of Ch. intermedia Boiss. and C. ruthenica Lam., determination of pharmacological activity to substantiate the possibility of using these plants as medicinal raw materials. METHODS: The antitumor activity of grossheimin was studied in white outbred rats and mice in 12 strains of transplanted tumors. The antiparasitic activity of grossheimin and cynaropicrin was studied during replication of models of experimental opisthorchiasis on male golden hamsters (Mesocricetus auratus) of the SPF category. Experiments in vivo were carried out on pastoral dogs infested with various types of helminths. The hypolipidemic activity of grossheimin was studied in experimental rats with a single intragastric administration of ethanol, causing acute hyperlipidemia. The antimicrobial activity of cynarpicrin was determined in relation to test strains of Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis and Gram-negative strains of Escherichia coli and Pseudomonas aeruginosa by the method of diffusion in agar. RESULTS: Characteristic diagnostic features for Ch. intermedia Boiss. and C. ruthenica Lam. were revealed, which make it possible to diagnose and standardize the medicinal plants under study. Pharmacological studies have shown that grossheimin and cynaropicrin have antitumor, antiparasitic, hypolipidemic, and antimicrobial activity. Grossheimin significantly inhibits the growth of sarcoma 180, Pliss lymphosarcoma, and Ehrlich’s solid tumor. On the model of acute hyperlipidemia caused by the introduction of ethanol, grossheimin had a hypolipidemic effect, reducing the serum levels of triacylglycerides, total cholesterol, and low-density lipoprotein cholesterol. Under in vitro conditions, grossheimin and cynaropicrin exhibited anthelmintic action against Opisthorchis felineus worms, and under in vivo conditions, cynaropicrin was up to 100% effective against tapeworm infections (Taenia sp.). CONCLUSION: It was determined that the quantitative yield of sesquiterpene lactones is provided by extraction of plant raw materials with an ethanol: water (1:1) mixture under the action of ultrasound. Characteristic diagnostic features for C. intermedia Boiss. and C. ruthenica Lam. were revealed, which make it possible to diagnose and standardize the medicinal plants under study.

Lactucin induces apoptosis through reactive oxygen species-mediated BCL-2 and CFLARL downregulation in Caki-1 cells.

Lactucin, a naturally occurring active sesquiterpene lactone, is abundantly found in chicory and romaine lettuce. A recent study reported that lactucin could induce apoptosis in leukemia cells. However, its cytotoxicity and potential molecular mechanisms underlying cancer cell death remain unclear. Therefore, in this study, we aimed to investigate the direct effect and underlying mechanism of action of lactucin on renal cancer cells. MTT assay and flow cytometry were performed to evaluate the rate of cell proliferation and apoptosis, respectively. Western blotting, reverse transcription polymerase chain reaction, and protein stability analyses were performed to analyze the effect of lactucin on the expression of apoptosis-related proteins such as B-cell lymphoma 2 (BCL-2) and CFLAR (CASP8 and FADD like apoptosis regulator) long isoform (CFLARL) in Caki-1 human renal cancer cells. In addition, reactive oxygen species (ROS) generation was evaluated using flow cytometry. Lactucin treatment induced apoptosis in Caki-1 cells in a dose-dependent manner via activation of the caspase pathway. It downregulated BCL-2 and CFLARL expression levels by suppressing BCL-2 transcription and CFLARL protein stability, respectively. Pretreatment with N-acetyl-1-cysteine, a ROS scavenger, attenuated the lactucin-induced apoptosis and restored the BCL-2 and CFLARL expression to basal levels. Lactucin-facilitated BCL-2 downregulation was regulated at the transcriptional level through the inactivation of the NF-κB pathway. Our study is the first to demonstrate that lactucin-induced apoptosis is mediated by ROS production, which in turn activates the caspase-dependent apoptotic pathway by inhibiting BCL-2 and CFLARL expression in Caki-1 cells.

Xanthatin inhibits human colon cancer cells progression via mTOR signaling mediated energy metabolism alteration.

Tumor cells exhibit higher glycolysis and rely on abnormal energy metabolism to produce ATP, which is essential for cell proliferation and migration. Abnormal energy metabolism inhibition is considered a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. This study evaluated the effect of xanthatin on the energy metabolism of human colon cancer cells. The results showed that xanthatin significantly inhibited the migration and invasion of human HT-29 and HCT-116 colon cancer cells. We found that xanthatin effectively reduced the production of ATP and promoted the accumulation of lactate. Xanthatin inhibited glycolysis which may be related to the reduction of glucose transporter 1 (Glut1) and monocarboxylate transporter 4 (MCT4) mRNA and protein levels. Concomitantly, xanthatin promoted complex II activity and oxidative phosphorylation (OXPHOS), resulting in mitochondrial damage and cell death in HT-29 cells. Furthermore, xanthatin inhibited the phosphorylation of mTOR, the phosphorylation of 4E-binding protein 1 (4E-BP1) and c-myc in HT-29 cells. Moreover, rapamycin, a mTOR inhibitor, could enhance the cytotoxicity effect in xanthatin treated HT-29 cells. Additionally, HT-29 cells transfected with si-mTOR aggravated xanthatin induced cell viability inhibition. Based on these results, we observed that the effect of xanthatin on energy metabolism may be related to its inhibition of the mTOR signaling pathway. Collectively, this study provides important insights into xanthatin's anticancer effect, which occurs by regulation of the energy metabolism of human colon cancer cells, and suggest that xanthatin has potential as a botanical drug against abnormal tumor energy metabolism.

Atividade antimicrobiana das lactonas sesquiterpênicas da folha da yacon (Smallanthus sonchifolius, Asteraceae)

A yacon (Smallanthus sonchifolius) é uma planta originária dos Andes pertencente à família Asteraceae. Seus tubérculos e folhas são consumidos de forma medicinal, principalmente para o controle da hiperglicemia. Adicionalmente, os tricomas glandulares presentes nas folhas são ricos em lactonas sesquiterpênicas (LST) como a enidrina, uvedalina e sonchifolina, que apresentam atividade antimicrobiana contra diferentes fungos e bactérias gram-positivas. No presente trabalho avaliou-se a atividade antimicrobiana das LST extraídas das folhas da yacon frente à cepas de Candida albicans, Candida tropicalis, Staphylococcus aureus e Salmonella enterica Typhimurium pelo método de difusão em disco. Encontrou-se atividade antimicrobiana contra S. aureus. Seguiu-se com o teste de microdiluição, que determinou uma concentração inibitória mínima de 0,09 mg/ml contra S. aureus. Os resultados confirmam o potencial antimicrobiano das lactonas sesquiterpênicas, especialmente contra bactérias gram-positivas.

NMR Based Metabolic Profiling of Saussurea lappa Roots and Aerial Parts from Western Himalaya

Saussurea lappa (Decne.) Sch. Bip (kuth) is a well known medicinal plant of the western Himalayan region, used in oriental medicines to treat diverse complaints. In the present study, polar and non- polar fractions of ethanolic extracts of S. lappa (aerial parts and roots) were taken for detailed profiling using NMR. Fifty-six compounds of different classes were unambiguously identified with the use of 1D and 2D NMR and quantified by a relative quantification method. Metabolites belonging to diverse classes, including sesquiterpene lactones, steroids, triterpenoids, phenolics, carbohydrates, organic and amino acids were identified. Roots were enriched with sesquiterpene lactones and phenolics. Triterpenoids and steroids were dominating in the aerial parts. Biologically active sesquiterpene lactones including alantolactone, isoalantolactone, dehydrocostus lactone and costunolide were observed as 121.7±1.5, 111.7±0.6, 82.5±2.0 and 42.6±1.4 mg/g dried wt. respectively in S. lappa roots. The simultaneous presence of these four important marker compounds in the chloroform fractions of roots were the major finding of this study. Health care metabolites, myoinositol (66.97±3.0 mg/g), and choline (13.74±0.08 mg/g) were also detected in aqueous fraction of S. lappa aerial parts. NMR-based comprehensive metabolite information was used to develop the chemical signature, quality control chemical markers, and strategies to understand the chemical diversity of S. lappa.

Sesquiterpene Lactones from Calea pinnatifida: Absolute Configuration and Structural Requirements for Antitumor Activity.

This work describes the chromatographic fractionation of the aerial parts of Calea pinnatifida and the structural characterization and determination of the absolute configuration of the isolated compounds as well as their antitumor potential. The HPLC fractionation of the CH2Cl2 phase of the MeOH extract from the leaves of C. pinnatifida led to the isolation of two related sesquiterpene lactones (STLs): calein C (1) and calealactone B (2). Additionally, during the purification process, a derivative of calein C (3) was formed as a product of the Michael addition of MeOH. The structures of Compounds 1–3 were established based on spectroscopic and spectrometric data, while the absolute stereochemistry was established by vibrational circular dichroism. In order to evaluate the effect of the conjugated double bonds on the cytotoxic activity of STLs, Compounds 1–3 were tested against anaplastic (KTC-2) and papillary (TPC-1) thyroid carcinoma cells. Calein C was the most active of the STLs, and displayed activity against both KTC-2 and TPC-1. On the other hand, the calein C derivative (3) was the least cytotoxic of all the compounds tested. These results are promising and suggest the importance of studying sesquiterpene lactones isolated from C. pinnatifida in terms of antitumor activity, especially considering the effects of α,β-unsaturated carbonyl systems.

Trypanocidal activity of South American Vernonieae (Asteraceae) extracts and its sesquiterpene lactones

Chagas disease is caused by Trypanosoma cruzi and affects the poorest population in the Americas. Fourteen plant extracts and seventeen sesquiterpene lactones from the tribe Vernonieae (Asteraceae), were evaluated for the first time against T. cruzi. Cytotoxicity employing HeLa cells was also assessed. The best results were obtained with leaves and flowers rinse extracts from Vernonanthura nebularum (E-1 and E-3) and Elephantopus mollis (E-11 and E-13), with IC50 values <2 µg/mL, being E-1 the most active (IC50 = 0.8 µg/mL). Additionally, these extracts displayed a good selectivity (SI > 10). The most active sesquiterpene lactones, isolated from the extracts, were 2 (2-methoxy-2,5-epoxy-8-methacryloxygermacra-3Z,11(13)-dien-6,12-olide) and 6 (2-ethoxy-2,5-epoxy-8-angeloxygermacra-3Z,11(13)-dien-6,12-olide) from V. nebularum and 12 (8α-methacryloxyhirsutinolide 13-O-acetate) from V. pinguis, with IC50 of 1.5, 2.1 and 2.0 µM, respectively. These compounds showed SI values >14, better than those of the reference drug nifurtimox. Plants living in South American ecosystems could become a potential source of trypanocidal agents.

Costunolide inhibits osteosarcoma growth and metastasis via suppressing STAT3 signal pathway

Costunolide, an active sesquiterpene lactone, is derived from a number of medicinal plants and it exhibits a broad spectrum of bioactivities such as anti-inflammatory and potential anti-tumor activity. However, its effects on human osteosarcoma and the underlying mechanisms have not yet been evaluated. Here, we found Costunolide inhibits STAT3 transcriptional activity and the expression level of phospho-STAT3 (Tyr-705). Furthermore, we found Costunolide suppresses STAT3 downstream target genes expression. Finally, our data demonstrated Costunolide inhibits osteosarcoma growth and metastasis in vitro and in vivo. Therefore, our studyprovided the first evidence that Costunolide inhibits osteosarcomagrowth and metastasis by impairing STAT3 signal pathway and Costunolide is a potential candidate in osteosarcoma therapy.

Antitumor activity of alantolactone in lung cancer cell lines NCI-H1299 and Anip973.

Alantolactone is a sesquiterpene lactone extracted from Inula helenium L. plants possessing many biological activities, including anti-inflammatory, antiproliferation, and antimicrobial. The inhibitory effects and the underlying mechanisms of alantolactone on lung cancer cells NCI-H1299 and Anip973 were investigated in this study. The results showed that alantolactone could decrease cell viability and induce cell apoptosis of NCI-H1299 and Anip973. After the cells were treated with alantolactone, the expression of Bcl-2 decreased, while the expression of Bax increased, the expression of MMP-9, MMP-7, and MMP-2 gradually decreased after alantolactone treatment. Furthermore, results showed that alantolactone could activate p38 MAPK pathway and suppress NF-κB pathway, which are involving in lung cancer development. These results indicated that alantolactone was a potential agent for lung cancer treatment. PRACTICAL APPLICATIONS: Lung cancer is one of the most common contributors of cancer death in the world. Chemoprevention and chemotherapy with natural substances are prospective methods for lung cancer treatment. In recent years, the anti-cancer activity of various sesquiterpene lactones has attracted a great deal of interest. Alantolactone is the major active sesquiterpene lactones isolated from Inula helenium L, which is used as a medicine in ancient Romans due to wide range of pharmacological activities. The results obtained from this study revealed the inhibitory effects of alantolactone on lung cancer cells and might provide some experimental basis for prevention and treatment of lung cancer with alantolactone.

Production Technologies of Pharmacologically Active Sesquiterpene Lactones

Sesquiterpene lactones form a large group belonging to natural terpenoids series, generally found in plants of Asteraceae family and exhibiting anti-tumor, antiviral, immunostimulant, antifungal, antimicrobial, anti-inflammatory, antimutagenic, growth stimulating, antifeedant effects. Therefore, search for new compounds with a broad spectrum of pharmacological activity in this series provides the opportunities for effective and conceptually new drug design. The basis of the technology for the isolation of sesquiterpene lactones is the extraction of raw materials with various organic solvents, followed by chromatographic purification. Sesquiterpene lactones have no common properties that can be used in their isolation. Some of them are well soluble in non – polar solvents, others-only in polar, in this regard, the methods of isolation of sesquiterpene lactones are diverse. The greatest number of sesquiterpene lactones is isolated from leaves and flowers, slightly less – from roots and bark. Therefore, the development of methods for their isolation is associated with the selection of solvents and optimization of the extraction mode. Unfortunately, very few medicines based on sesquiterpene lactones are produced by the pharmaceutical companies today. Complexity of introduction of pharmacologically active sesquiterpene lactones technology into pharmaceutical production is in imperfection of their isolation methods from plant raw material, their purification and separation from obtained extracts. Production technologies of the patented medicines "Santonin", "Alanton" on the basis of sesquiterpene lactones are multiphase, labor-intensive, implying the use of many toxic organic solvents which is against the international GMP standards.

Metabolism and pharmacokinetics of alantolactone and isoalantolactone in rats: Thiol conjugation as a potential metabolic pathway.

Alantolactone (AL) and isoalantolactone (IAL), two major active sesquiterpene lactones isolated from Radix Inulae extract, have a wide range of pharmacological activities. The predominant metabolic pathway of AL and IAL observed was glutathione (GSH) conjugation in vitro, which could occur in the absence of metabolic enzymes. Non-enzymatic conjugation with cysteine (Cys) couldalso be observed. Four metabolites (AL-GSH, AL-Cys, IAL-GSH, IAL-Cys) were subsequently isolated and confirmed by nuclear magnetic resonance (NMR). The results indicated that the thiol of GSH or Cys can be reacted with the exomethylene carbon atoms of α, β-unsaturated carbonyl of AL and IAL. After intravenous administration in rats, AL and IAL were extensively metabolized, and the exposure, as measured by area under the concentration-time curve (AUC), for AL-GSH, AL-Cys, IAL-GSH, and IAL-Cys was approximately 1.54-, 0.96-, 1.50-, and 0.91-fold that of the parent drug, respectively. The AUC ratio of metabolites to parent compounds of oral administration was 3.66-, 9.19-, 12.97-, and 9.92-fold that of the parent drug for the above metabolites, respectively. The bioavailability of AL-total (AL, AL-GSH, AL-Cys) and IAL-total (IAL, IAL-GSH, IAL-Cys) was, respectively, 8.39% and 13.07%, which was 3.62- and 6.95- fold that of AL (2.32%) and IAL (1.88%), respectively. The oral exposure will be underestimated if the parent drugs are tested alone. These findings provide useful information for preclinical safety evaluation, and for predicting AL and IAL metabolism in humans.

Structural Analysis and Biological Activities of Sesquiterpene Lactones Isolated from the Leaves and Stems of Chrysanthemum boreale Makino

Structural Analysis and Biological Activities of Sesquiterpene Lactones Isolated from the Leaves and Stems of Chrysanthemum boreale Makino

Screening of several biological activities induced by different sesquiterpene lactones isolated from Centaurea behen L. and Rhaponticum repens (L.) Hidalgo

This study aims to evaluate the in vitro cytotoxic, in vitro and in ovo anti-angiogenic effects and antimicrobial activity of sesquiterpene lactones (SLs) from two plants Centaurea behen and Rhaponticum repens (L.). Five SLs, including cynaropicrin (1), 4β,15-dehydro-3-dehydrosolstitialin A (2), aguerin B (3), janerin (4), cebellin E (5), and a flavone hispidulin (6) were isolated from C. behen (compounds 1–3) and R. repens (compounds 4–6). Cynaropicrin (1) and aguerin B (3) were characterised by strong cytotoxic activities against A2780 cells with IC50 values of 1.15 and 1.62 μg mL−1, respectively, comparable to that of doxorubicin (IC50 = 1.17 μg mL−1). The anti-angiogenic study showed the remarkable inhibitory effect of cynaropicrin (1) and aguerin B (3) on the proliferation and migration of HUVECs. In addition, cynaropycrin and aguerin B exhibited significant angio-inhibitory effects in CAM assay. These findings may be useful for the development of novel chemotherapeutic agents for the treatment of cancer.

The Joint Action of Sesquiterpene Lactones from Leaves as an Explanation for the Activity of Cynara cardunculus.

The work described herein is a continuation of a previous study centered on the bioprospect of cardoon (Cynara cardunculus) leaf extracts through the isolation of secondary metabolites with phytotoxic activity. Chromatographic fractionations of the ethyl acetate extract and spectroscopic analysis showed that the majority of the components were sesquiterpene lactones. Of these compounds, aguerin B, grosheimin, and cynaropicrin were very active on etiolated wheat coleoptile, standard target species, and weed growth. The joint action of binary mixtures of these three active sesquiterpene lactones and one nonactive compound (11,13-dihydroxy-8-desoxygrosheimin) was studied. The activities of fixed-ratio mixtures were assessed on wheat coleoptile. The results can be interpreted with respect to a reference model by considering dose-response analyses and isobolograms with linear regression analyses. A total of 17 binary mixtures at different levels of inhibition (ED25, ED50, and ED75) were studied, and predominantly they responded additively (25). Deviations from additivity included seven synergistic responses and two antagonistic responses. The joint action of major sesquiterpene lactones isolated from C. cardunculus can explain the activities observed in extracts and fractions. The results reported here reiterate the utility of the wheat coleoptile bioassay as a quick tool to detect potential synergistic effects in binary mixtures.

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

Parthenolide (PTL), a major active sesquiterpene lactone from the herbal plant Tanacetum parthenium, has been applied in traditional Chinese medicine for centuries. Although PTL demonstrates potent anticancer efficacy in numerous types of malignant cells, the cellular targets of PTL have not been well defined. We reported here that PTL interacts with both cytosolic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2), two ubiquitous selenocysteine-containing antioxidant enzymes, to elicit reactive oxygen species-mediated apoptosis in HeLa cells. PTL selectively targets the selenocysteine residue in TrxR1 to inhibit the enzyme function, and further shifts the enzyme to an NADPH oxidase to generate superoxide anions, leading to reactive oxygen species accumulation and oxidized thioredoxin. Under the conditions of inhibition of TrxRs in cells, PTL does not cause significant alteration of cellular thiol homeostasis, supporting selective target of TrxRs by PTL. Importantly, overexpression of functional TrxR1 or Trx1 confers protection, whereas knockdown of the enzymes sensitizes cells to PTL treatment. Targeting TrxRs by PTL thus discloses an unprecedented mechanism underlying the biological activity of PTL, and provides deep insights to understand the action of PTL in treatment of cancer.

Costunolide, an active sesquiterpene lactone, induced apoptosis via ROS-mediated ER stress and JNK pathway in human U2OS cells.

Costunolide, an active sesquiterpene lactone, is derived from many herbal medicines and it exhibits a broad spectrum of bioactivities such as anti-inflammatory, potential anti-tumor activity. Herein we assessed the anti-cancer effects of costunolide on U2OS cells and explored the underlying molecular mechanisms. The experiment data show that Costunolide exhibited significant anti-tumor activity by apoptosis related assays including Annexin V-FITC/PI flow cytometric analysis and 4,6-diamino-2-phenyl indole (DAPI) staining morphological analysis. Furthermore, we found Costunolide induced the loss of mitochondrial transmembrane potential, down-regulated Bcl-2/Bax ratio, encouraged Cyt-c release and caspase activation. All those effects are contributed by reactive oxygen species (ROS) generation and ER stress-induced mitochondrial dysfunction which are also responsible for c-Jun N-terminal kinase (JNK) activation. After the treatment of JNK inhibitor SP600125, it obviously reversed costunolide-induced apoptosis. Given N-acetyl-l-cysteine (NAC) effectively blocked the activation of JNK. Taken together, our results demonstrate that costunolide induces apoptosis in human U2OS cells through ROS generation and p38 MAPK/JNK activation.

Costunolide induces lung adenocarcinoma cell line A549 cells apoptosis through ROS (reactive oxygen species)-mediated endoplasmic reticulum stress.

Costunolide is an active sesquiterpene lactone derived from many herbal medicines. It has a broad spectrum of bioactivities, including anti-inflammatory and potential anti-tumor effects. The aims of the present study were to evaluate the inhibitory effects of costunolide on A549 cell growth and to explore the underlying molecular mechanisms. Annexin V-FITC/PI flow cytometry analysis revealed that costunolide induced apoptosis. To study the mechanism, we found that costunolide exposure activated the unfolded protein response (UPR) signaling pathways, as shown by the up-regulation of GRP78 and IRE1α and the activation of ASK1 and JNK. Meanwhile, siRNA knockdown of IRE1α significantly attenuated costunolide-induced apoptosis and partly restored the mitochondrial membrane potential. ER stress-activated JNK phosphorylated Bcl-2 at Ser70, which changes the anti-apoptotic function of Bcl-2, resulting in mitochondrial dysfunction and leading to mitochondrial activation of apoptosis. Furthermore, costunolide induced ROS generation, while the antioxidant N-acetyl cysteine (NAC) effectively blocked ER stress and apoptosis activation, suggesting that ROS acts as an upstream signaling molecule in triggering ER stress and mitochondrial apoptotic pathways. Taken together, our research demonstrates that costunolide exhibits its anti-tumor activity though inducing apoptosis, which is mediated by ER stress. We further confirm that Bcl-2 is a key molecule connecting the ER stress and mitochondrial pathways.