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Xanthium strumarium´s xanthatins induces mitotic arrest and apoptosis in CT26WT colon carcinoma cells
... In view of the promising results obtained in vitro, we used a mouse model lung metastasis produced by CT26WT tumor cells to evaluate the in vivo effect of Xanthium strumarium. The CT26WT cell line was chosen because the antiproliferative activity of WEXs and XFC were previously demonstrated [50]. The MTT assays determined the anti-proliferative effects on CT26WT cell growth after 24 h of treatment. ...
... The MTT assays determined the anti-proliferative effects on CT26WT cell growth after 24 h of treatment. There results showed that WEXs and XFC produced inhibitory effects on CT26WT cell growth in a concentration-dependent manner with IC 50 values of 26.8 μg/ml and 25.4 μg/ml respectively [50]. ...
... One explanation for this effect could be that the metabolites present in this plant are able to inhibit cell adhesion molecules (CAMs), which facilitate neoplastic adhesion and migration and, thus, invasion of other organs and tissues [51]. The closest antitumor impact and concentrations extrapolation one can perform at this point are provided in the study by Piloto-Ferrer et al. [50], which tested the in vivo antitumor impact of XFC to that of xanthatins fractionated from XFC in a colorectal syngeneic model. The authors elegantly demonstrated that daily administration for 15 days of 100 mg/kg XFC or of 5 mg/kg of xanthatins enriched fraction efficiently reduced tumor volumes to levels similar to that of a platinum chemotherapy drug at 6 mg/kg Oxaliplatin [50]. ...
The antiproliferative activity of Xanthium strumarium L. extract (XFC), a traditional herbal medicine, is believed to alter the cell mitotic machinery, but the molecular mechanisms underlying its anticancer actions remain poorly characterized. We found that XFC exerted significant in vitro cell proliferation inhibitory effect against the ovarian, breast, and colon cancer cell line models tested. In vitro, XFC efficiently targeted both the cytotoxic drug chemoresistance phenotype of SKOV-3 and ES-2 ovarian cancer cells. Early apoptosis and late apoptosis were effectively induced by XFC extract in ES-2 cells, whereas late apoptosis and necrosis events were triggered in SKOV-3 cells. Cell cycling regulation was trapped by XFC extract in the G2/M phase in both the ES-2 and SKOV-3 cell models. This effect was, in part, attributable to increased dose-dependent tubulin polymerization, which was increased in SKOV-3 cells. Whereas XFC extract triggered poly (ADP-Ribose) polymerase (PARP) cleavage in both ES-2 and SKOV-3 cells, it only lowered Nrf2 in ES-2 cells and phosphorylated Akt levels in SKOV-3 cells. Interestingly, cell cycling regulators Cdk4, Cyclin D3, and p27 were all decreased in SKOV-3 cells. XFC extracts were effective in inhibiting in vitro migration in both ovarian cancer cell models. In addition, we found promising in vivo results when XFC exhibited significant antimetastatic action in a mouse model of colon cancer. Such in vitro and in vivo evidence confirm that XFC has excellent anti-tumor activity, and represents a potential promising source of anticancer agents in the targeting of the chemoresistance phenotype and of metastasis in human ovarian and colon cancers.
... These compounds have been reported to exhibit numerous biological activities, some of which include antioxidant, antibacterial, anti-inflammatory, and antitumor activities as well as neuroprotective effects [5]. Xanthatin has also been reported to inhibit both tumor growth and cell proliferation in various types of cancer cell lines [8][9][10]38,39]. ...
... Interestingly, further purification of the ethyl acetate fraction yielded subfractions that lost their anticancerous properties, reiterating that the combination of different compounds is responsible for the inhibitory effect [38]. Slightly higher cytotoxicity than of the whole crude extract of X. strumarium L. leaves was also for a chloroform fraction by Piloto-Perrer et al. in CT26WT colon carcinoma cells [9]. Besides the evaluation of whole crude extracts, many scientific papers tried to fractionate crude extracts and isolate compounds with antitumoral activities from different parts of X. strumarium L. [10,49,[53][54][55][56][57]. ...
One of the objectives of this study consists of the assessment of the antitumor activity of several extracts from three selected plant species: Xanthium spinosum L., Trifolium pratense L., and Coffea arabica L. and also a comparative study of this biological activity, with the aim of establishing a superior herbal extract for antitumor benefits. The phytochemical profile of the extracts was established by HPLC-MS analysis. Further, the selected extracts were screened in vitro for their antitumor activity and antioxidant potential on two cancer cell lines: A549—human lung adenocarcinoma and T47D-KBluc—human breast carcinoma and on normal cells. One extract per plant was selected for in vivo assessment of antitumor activity in an Ehrlich ascites mouse model. The extracts presented high content of antitumor compounds such as caffeoylquinic acids in the case of X. spinosum L. (7.22 µg/mL—xanthatin, 4.611 µg/mL—4-O-caffeoylquinic acid) and green coffee beans (10.008 µg/mL—cafestol, 265.507 µg/mL—4-O-caffeoylquinic acid), as well as isoflavones in the case of T. pratense L. (6806.60 ng/mL—ononin, 102.78 µg/mL—biochanin A). Concerning the in vitro results, the X. spinosum L. extracts presented the strongest anticancerous and antioxidant effects. In vivo, ascites cell viability decreased after T. pratense L. and green coffee bean extracts administration, whereas the oxidative stress reduction potential was important in tumor samples after T. pratense L. Cell viability was also decreased after administration of cyclophosphamide associated with X. spinosum L. and T. pratense L. extracts, respectively. These results suggested that T. pratense L. or X. spinosum L. extracts in combination with chemotherapy can induce lipid peroxidation in tumor cells and decrease the tumor viability especially, T. pratense L. extract.
... The cytotoxic study of the vegetal extract from Xanthium chinese Mill (before known as Xanthium strumarium) performed by Sanchez-Lamar in 2016 [20], and Piloto-Ferrer in 2019 [21], using CHO and CT26WT cell lines, respectively, prove by the rst time that the phytocompounds present in this extract could disrupt with the assembly of the mitotic spindle by MTs destabilization. The chemical fractionation allows to identify as the principal responsible of this destabilizing effect the isomers xanthatin and 8-epixanthatin [20] (Fig. 1). ...
... Because of this, the search for new and more e cient CBS inhibitors continues to be an attractive open research eld. In a previous study, it was observed that mice treated with the chemical fraction containing the xanthanolides did not show signs of toxicity, but a signi cant inhibitory effect in the proliferation of the tumor [21]. These results could be related to the fact that xanthanolides have lower binding energy (-6.79 ...
Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro, related to the microtubules destabilizing properties of these phytocompounds. However, the exact binding pocket on tubulin of these isomers remains unknown. The aim of this work is, to develop a comprehensive computational strategy to understand and eventually predict the structure-activity relationship of xanthatin and 8- epi -xanthatin, with the destabilizing-antimitotic binding domain in tubulin heterodimer and to propose a putative binding site for these phytocompounds into the microtubule destabilizing agents binding sites in the tubulin heterodimer. A molecular docking was performed using the xanthanolides conformers as ligands and several tubulin structures obtained from the Protein Data Bank as receptor. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum and their stability was evaluated by solvated molecular dynamics simulations during 100 ns. Xanthanolides showed higher stability into the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, the xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity.
... [1] Modern pharmacological research has shown that XF also exerts hypoglycemic, anti-inflammatory, and other effects. [2][3][4] Although XF has high efficacy, its toxicity cannot be ignored. Cases of poisoning induced by accidental ingestion of XF are often reported, mainly resulting from drug-induced liver injury. ...
... In addition to its effects on human liver cancer cells, XF drug serum displayed clear toxic and inhibitory effects on human brain glioma and S180 sarcoma cells. [4] Hypoglycemic effect ...
... Collectively, these data suggest that XFC contains anticancer molecules that could efficiently target crucial cell cycle division processes, which regulate chemoresistance. e closest antitumor impact and concentrations extrapolation one can perform at this point is provided from a recent study, which tested the in vivo antitumor impact of XFC to that of xanthatins fractionated from XFC in a colorectal xenograft model [47]. e authors elegantly demonstrated that daily administration for 15 days of 100 mg/kg XFC or of 5 mg/kg of xanthatins enriched fraction efficiently reduced tumor volumes to levels similar to that of a platinum chemotherapy drug at 6 mg/kg Oxaliplatin [47]. ...
... e closest antitumor impact and concentrations extrapolation one can perform at this point is provided from a recent study, which tested the in vivo antitumor impact of XFC to that of xanthatins fractionated from XFC in a colorectal xenograft model [47]. e authors elegantly demonstrated that daily administration for 15 days of 100 mg/kg XFC or of 5 mg/kg of xanthatins enriched fraction efficiently reduced tumor volumes to levels similar to that of a platinum chemotherapy drug at 6 mg/kg Oxaliplatin [47]. ...
Emerging drugs aim at targeting the genomic integrity and replication machinery in ovarian cancer. While the antiproliferative activity of Xanthium strumarium L. extract (XFC), a traditional herbal medicine, is believed to alter the mitotic apparatus of Chinese hamster ovary epithelial cells, its capacity to target and overcome the chemoresistance phenotype in ovarian cancer is unknown. Among the cancer cell lines tested, we found that the best proliferation inhibitory effect for XFC was against ovarian cancer cells and ranged from 30 to 35 μ g/mL. XFC efficiently targeted both the cytotoxic drug chemoresistance phenotype of SKOV-3 cells and of the chemosensitive ES-2 cells. Early apoptosis and late apoptosis were effectively induced by XFC extract in ES-2 cells, whereas late apoptosis and necrosis events were triggered in SKOV-3 cells. Cell cycling regulation was trapped by XFC extract in the G2/M phase in both the ES-2 and SKOV-3 cell models. This effect was, in part, attributable to increased dose-dependent tubulin polymerization, which was increased in SKOV-3 cells. Whereas XFC extract triggered poly (ADP-Ribose) polymerase (PARP) cleavage in both ES-2 and SKOV-3 cells, it only lowered Nrf2 in ES-2 cells and phosphorylated Akt levels in SKOV-3 cells. Interestingly, cell cycling regulators Cdk4, Cyclin D3, and p27 were all decreased in SKOV-3 cells. XFC extracts were effective in inhibiting in vitro migration in both ovarian cancer cell models. Our data support the potential anticancer targeting of chemoresistant human ovarian cancer cells phenotype by XFC extract.
... Xanthatin is a sesquiterpene lactone ( Figure 5) derived from Xanthiun strumarium L. and exerts cytotoxic effect on cancer cells [168,169]. Since the identification of the biological properties of xanthatin, its anti-cancer effects have been demonstrated in various cancer systems such as breast cancer [170][171][172][173], gastric carcinoma [174], lung cancer [175][176][177][178], melanoma [179], colon cancer [180][181][182][183], hepatocellular carcinoma [184][185][186], pancreatic cancer [187], and glioma [188,189]. Xanthatin induces cellular apoptosis through mitochondrial ROS accumulation and the dysregulation of redox balance [178]. ...
The relationship between oxidative stress and cancer has been extensively studied and highlighted, along with its role in various aspects of angiogenesis. The modulation of oxidative levels and the adaptive mechanisms of oxidative stress in cancer systems are attractive research themes for developing anti-cancer strategies. Reactive oxygen species (ROS) are involved in various pathophysiological processes and play crucial roles in DNA damage and angiogenesis. Although cancer cells have developed various adaptive defense mechanisms against oxidative stress, excessive ROS production has been proposed as an anti-cancer strategy to induce cellular apoptosis. In particular, natural-source-based antioxidants have been identified as effective against cancers, and various delivery platforms have been developed to enhance their efficacy. In this review, we highlighted the anti-cancer components (plumbagin, quercetin, resveratrol, curcumin, xanthatin, carvacrol, telmisartan, and sulforaphane) that modulate ROS levels and the recent targeting platforms used to increase the application of anti-cancer drugs and the developed delivery platforms with diverse mechanisms of action. Further, we summarized the actual doses used and the effects of these drug candidates in various cancer systems. Overall, this review provides beneficial research themes for expanding cancer-targeting fields and addressing limited applications in diverse cancer types.
... Many xanthanolides serve as leading structures in drug discovery (Lei et al., 2019). For instance, both tomentosin and 8-epi-xanthatin display anticancer properties by arresting tumor cell mitosis (Piloto-Ferrer et al., 2019;Rozenblat et al., 2008). Their physiological roles in plants have also been implicated (Frey et al., 2024). ...
Xanthanolides, also described as seco‐guaianolides, are unique sesquiterpene lactones (STLs) with diverse bioactivities. Most of xanthanolides are 12,8‐olides based on the position of their lactone ring. The biosynthetic pathway leading to xanthanolides has hitherto been elusive, especially how nature creates the xanthane skeleton is a long‐standing question. This study reports the elucidation of a complete biosynthetic pathway to the important 12,8‐xanthanolide 8‐ epi ‐xanthatin. The xanthane‐type backbone is directly derived from the central precursor germacrene‐type sesquiterpene, germacrene A acid, via oxidative rearrangement, catalyzed by an unusual cytochrome P450. Subsequently, a 12,8‐lactone ring is formed within this xanthane‐type backbone resulting in xanthanolides. The biosynthetic pathway for xanthanolides contrasts with the previously unified biosynthetic route for diverse 12,6‐guaianolides, in which a 12,6‐lactone ring formation precedes the transformation of a germacrene‐type skeleton into a guaiane‐type structure. The discovery of the full biosynthetic pathway of 8‐ epi ‐xanthantin opens new opportunities for producing xanthanolides in microbial organisms using synthetic biology strategies.
... Para evaluar la actividad antiproliferativa del extracto de P. comosus, se utilizó el ensayo clonogénico descrito por Piloto-Ferrer con algunas modificaciones. (9) Para ello se sembraron 3 x10 3 células/mL de las tres líneas celulares en placas (Costar) de 12 pocillos en medio Medio Mínimo Esencial con 1 % de solución de aminoácidos no esenciales y 2 mM glutamina (Gibco TM ) suplementado con 10 % de SFBI (Gibco TM ) y fueron incubadas a 37 ºC en atmósfera de 5 % de CO2 durante 6 h. Tras la adhesión de las células se adicionaron 1,5 mL de extracto a tres concentraciones no citotóxicas, 150; 75 y 37,5 μg/mL (2 pocillos para cada concentración). ...
Introducción:
Desde los inicios de la medicina antigua, las plantas han sido utilizadas como tratamiento en diversas enfermedades incluyendo las de naturaleza infecto-contagiosa y el cáncer. Son numerosos los informes sobre las propiedades biológicas del género Phyllanthus.
Objetivo:
Evaluar la actividad citotóxica y antiproliferativa de un extracto acuoso de Phyllanthus comosus en tres líneas celulares, dos de origen tumoral (SiHa y HeLa) y una no tumoral (Vero).
Métodos:
La actividad citotóxica se evaluó mediante el método del MTT y la capacidad antiproliferativa mediante el ensayo de detección de inhibición de colonias o clonogénico. Se tuvieron en cuenta valores como la concentración citotóxica media (CC50), índice selectivo y porcentaje de disminución de la proliferación celular.
Resultados:
En el ensayo de citotoxicidad se obtuvieron CC50 similares para ambas líneas tumorales; mientras que el valor para la línea Vero resultó tres veces menos tóxico, con valores de índice de selectividad mayor que tres. El ensayo clonogénico demostró inhibición de la proliferación en las líneas tumorales, mientras que en células Vero no se observó inhibición de la capacidad de formación de colonias.
Conclusiones:
El extracto de P. comosus es más citotóxico para las líneas tumorales SiHa y HeLa que para las células Vero, no tumorales. Además, la inhibición de la formación de clonos celulares en ambas líneas tumorales evidencia su acción antiproliferativa y selectiva, lo que argumenta su potencialidad antitumoral in vitro
... In another study using C6 orthotopic models, xanthatin administration remarkably reduced glioma tumor growth and the vascular permeability highlighting the antiangiogenic effect of this natural product [159]. In addition, X. strumarium extract containing xanthatin and its analogue 8-epi-xanthatin delayed CRC tumor and reduced the number of lung metastasis via induction of apoptosis [160]. ...
Introduction
Sesquiterpene lactones (SLs) are one of the most diverse bioactive secondary metabolites found in plants and exhibit a broad range of therapeutic properties in several diseases. SLs have been showing promising potential in cancer clinical trials, and the molecular mechanisms underlying their anticancer potential are being uncovered. Recent evidence also points to a potential utility of SLs in cancer prevention.
Areas covered
This work identifies and evaluates SLs with promising anticancer potential based on cell, animal, and clinical models: Artemisinin, micheliolide, thapsigargin dehydrocostuslactone, arglabin, parthenolide, costunolide, deoxyelephantopin, alantolactone, isoalantolactone, atractylenolide 1, and xanthatin as well as their synthetic derivatives. We highlight actionable molecular targets and biological mechanisms underlying the anticancer therapeutic properties of SLs. This is complemented by a unique assessment of SL mechanisms of action that can be exploited in cancer prevention. We also provide insights into structure-activity and pharmacokinetic properties of SLs and their potential use in combination therapies.
Expert opinion
We extract seven major lessons learned and present evidence-based solutions that can circumvent some scientific limitations or logistic impediments in SL research and anticancer potential. SLs continue to be at the forefront of cancer drug discovery and are worth a joint interdisciplinary effort in order to leverage their promising potential in cancer therapy and prevention.
... The biological role of xanthatin is currently unclear, but it is implicated as an antifeedant in plant herbivore resistance [5]. In addition, it has shown inhibitory activities against several tumor cells, including breast cancer [6], colorectal cancer [7], and glioma cells [8]. In spite of many studies concerning the medical activities of xanthatin, the genes and enzymes involved in its biosynthesis are largely unknown [9]. ...
8,12-sesquiterpene lactones (STLs) are an important class of natural products with unique pharmaceutical activities. For years the pathway leading to 8,12-STLs remains an enigma. Xanthium strumarium accumulates abundant 8,12-STLs, and xanthatin is a characteristic 8,12-STL in it. Xanthatin has been previously postulated to be derived from germacrene A, but the steps from germacrene A to xanthatin are unknown. As part of an effort to understand the xanthatin biosynthetic pathway. This study reports the characterization of a unique germacrene A oxidase (XsGAO) from X. strumarium. Unlike a classical GAO enzyme, which is known to catalyze a three-step oxidation of germarene A to yield germacrene A acid (GAA), surprisingly, XsGAO catalyzed only one-step conversion of germacrene A to germacrene A alcohol. We discussed that GAO may be pressured to acquire a novel activity during the evolutionary path for the biosynthesis of 8,12-STLs.
... Mortality was monitored daily, and tumor growth was measured every 2 days during the entire treatment period (14 days). Tumor volume was calculated in accordance with Piloto-Ferrer et al. (2019). Finally, primary tumors were removed at the time of sacrifice (18 days after tumor cell inoculation), they were weighed and subsequently, they were fixed in 4% formaldehyde. ...
Ethnopharmacological relevance
Jarilla is the common name of an appreciated group of native plants from the semi-arid region in Argentina (Larrea cuneifolia Cav., Larrea divaricata Cav. and Zuccagnia punctata Cav.) that have been historically consumed to heal respiratory, musculoskeletal and skin ailments, as well as recommended for weakness/tiredness, hypertension, diabetes and cancer treatment. It was previously reported that some biological properties could be improved when these plants are used jointly. Infusions of a defined mixture, composed by three Jarilla species, L. cuneifolia: L. divaricata: Z. punctata (0.5:0.25:0.25) (HM2) showed synergistic and additive effect on antioxidant activity even after passing through the gastro-duodenal tract.
Aim of the study
The main purpose of this work was to evaluate antigenotoxic, antitumor, and anti-metastatic properties of the Jarilla species that grow in the Northwest of Argentina and a herbal combination of them.
Material and methods
Infusions of Jarilla mixture (HM2), and of each single plant species were prepared. Phenolic profiles of infusions were analyzed by HPLC-ESI-MS/MS and two relevant chemical markers were quantified. The antigenotoxic activity was evaluated by using the Ames test and the Cytokinesis-Block Micronucleus (CBMN) assay against direct mutagens. Evaluations of both cytotoxicity and antiproliferative effects were conducted on tumor and non-tumor cell lines. Both in vivo tumoral growth and metastasis inhibition were evaluated by using a carcinoma model on Balb/c mice.
Results
HM2 mix could suppress genetic and chromosome mutations induced by 4-nitro-o-phenylendiamine (4-NPD) and doxorubicin. Herbal mixture and single plant infusions showed cytotoxic effect against mammary, uterus, and brain tumoral cells without a selective action vs normal human cell line. HM2 mix was able to reduce mammary tumor mass on the Balb/c mice model and showed a significant reduction in the number of metastatic nodules in the lungs.
Conclusions
Our results suggest that the combinations of three Jarilla species from northwest Argentina would be a promising alternative to treat or slow down the development of chronic diseases, such as cancer.
... Previous research has shown that altered expression of particular genes may affect ESCC cell metastasis, invasion, apoptosis and proliferation [15][16][17] . Our results agree with the fact that carcinoma cell metastasis and invasion are closely associated with abnormal cell adhesion, endodermal cell division and nuclear division [18][19][20] . Extracellular matrix (ECM), is a critical component of the cancer cell niche, it can provide the tissue with the mechanical support and also mediate the cell-microenvironment interactions 21,22 . ...
Aberrant methylated genes (DMGs) play an important role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to integrate three cohorts profile datasets to ascertain aberrant methylated-differentially expressed genes and pathways associated with ESCC by comprehensive bioinformatics analysis. We downloaded data of gene expression microarrays (GSE20347, GSE38129) and gene methylation microarrays (GSE52826) from the Gene Expression Omnibus (GEO) database. Aberrantly differentially expressed genes (DEGs) were obtained by GEO2R tool. The David database was then used to perform Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses on selected genes. STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network, then the modules in the PPI networks were analyzed with MCODE and the hub genes chose from the PPI networks were verified by Oncomine and TCGA database. In total, 291 hypomethylation-high expression genes and 168 hypermethylation-low expression genes were identified at the screening step, and finally found six mostly changed hub genes including KIF14, CDK1, AURKA, LCN2, TGM1, and DSG1. Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process. After validation in multiple databases, most hub genes remained significant. Patients with high expression of AURKA were associated with shorter overall survival. To summarize, we have identified six feasible aberrant methylated-differentially expressed genes and pathways in ESCC by bioinformatics analysis, potentially providing valuable information for the molecular mechanisms of ESCC. Our data combined the analysis of gene expression profiling microarrays and gene methylation profiling microarrays, simultaneously, and in this way, it can shed a light for screening and diagnosis of ESCC in future.
Medicinal Plants: Microbial Interactions, Molecular Techniques, and Therapeutic Trends is a comprehensive exploration of the fascinating world of medicinal plants, their therapeutic advancements, and the application of molecular techniques to unlock their full potential. This book is structured into three illuminating sections, each shedding light on different facets of this rapidly developing field.
Section 1: Exploring Plant-Microbe Interactions
Covers the relationship between microbes and plants, the historical context and the pivotal role of microbes in shaping the future of medicinal plants. Discover the diverse array of bacteria associated with these plants and grasp their significance in enhancing the medicinal value of plants.
Section 2: Harnessing Molecular Techniques
Covers cutting-edge molecular techniques such as genome editing and modern breeding methods to optimize the genetic traits of medicinal plants. By understanding these techniques, readers will learn how to enhance plant growth, yield and quality.
Section 3: Nanotechnology for Therapeutic Enhancement
Covers nanotechnology and its transformative impact on medicinal plants. The section highlights emerging nano-engineering technology that can revolutionize the therapeutic properties of these plants.
Medicinal Plants: Microbial Interactions, Molecular Techniques, and Therapeutic Trends is a book for Interdisciplinary readers: students, scientists, academics, and industry professionals alike.
Whether you're a student, scientist, academic, or industry professional, this book is your gateway to the evolving world of plant-based medicine.
ContextPhytocompounds
xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro related to the microtubules destabilizing properties of these phytocompounds. Five binding sites for microtubule destabilizing agents have been characterized on tubulin by high-resolution X-ray crystallography: vinca domain, colchicine, pironetin, maytansine site, and more recently, the seventh site. This work aims to develop a comprehensive computational strategy to understand and eventually predict the interaction between xanthatin and 8-epi-xanthatin with the destabilizing-antimitotic binding domain of the tubulin heterodimer. In addition, we propose a putative binding site for these phytocompounds into the microtubule destabilizing binding sites on the tubulin heterodimer. Xanthanolides showed higher stability in the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, we found that xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity.Methods
The 3D structures for xanthatin and 8-epi-xanthatin were obtained using DFT with the hybrid functional B3LYP and the base 6-31G (d,p), implemented in Gaussian 09. The 3D coordinates for tubulin proteins were downloaded from PDB. The complexes tubulin-xanthanolides were predicted using a Monte-Carlo iterated search combined with the BFGS gradient-based optimizer implemented in the AutoDock Vina. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum, and their stabilities were evaluated by solvated molecular dynamics simulations during 100 ns. All molecular dynamics simulations were performed using the conjugate gradient method implemented in NAMD2 and CHARMM36 forcefield.
Purpose:
Retinoblastoma is the most common primary intraocular malignant tumor in children. Although intra-arterial chemotherapy and conventional chemotherapy have become promising therapeutic approaches for advanced intraocular retinoblastoma, the side effects threaten health and are unavoidable, making the development of targeted therapy an urgent need. Therefore, we intended to find a potential drug for human retinoblastoma by screening an in-house compound library that included 89 purified and well-characterized natural products.
Methods:
We screened a panel of 89 natural products in retinoblastoma cell lines to find the inhibitor. The inhibition of the identified inhibitor xanthatin on cell growth was detected through half-maximal inhibitory concentration (IC50), flow cytometry assay, and zebrafish model system. RNA-seq further selected the target gene PLK1.
Results:
We reported the discovery of xanthatin as an effective inhibitor of retinoblastoma. Mechanistically, xanthatin selectively inhibited the proliferation of retinoblastoma cells by inducing cell cycle arrest and promoting apoptosis. Interestingly, xanthatin targeted PLK1-mediated cell cycle progression. The efficacy of xanthatin was further confirmed in zebrafish models.
Conclusions:
Collectively, our data suggested that xanthatin significantly inhibited tumor growth in vitro and in vivo, and xanthatin could be a potential drug treatment for retinoblastoma.
Herbaceous annual plants of the genus Xanthium are widely distributed throughout the world and have been employed medicinally for millennia. This contribution aims to provide a systematic overview of the diverse structural classes of Xanthium secondary metabolites, as well as their pharmacological potential. On searching in various reference databases with a combination of three keywords “Xanthium”, “Phytochemistry”, and “Pharmacology”, relevant publications have been obtained subsequently. From the 1950s to the present, phytochemical investigations have focused mainly on 15 Xanthium species, from which 300 compounds have been isolated and structurally resolved, primarily using NMR spectroscopic methodology. Xanthium constituents represent several secondary metabolite types, including simple phenols, sulfur and nitrogen-containing compounds, lignans, sterols, flavonoids, quinones, coumarins, and fatty acids, with terpenoids being the most common of these. Among the 174 terpenoids characterized, xanthanolide sesquiterpenoids are abundant, and most of the compounds isolated containing sulfur were found to be new in Nature. The ethnomedical uses of Xanthium crude extracts are supported by the in vitro and in vivo effects of their constituents, such as cytotoxicity, antioxidant, antibacterial, antifungal, antidiabetes, and hepatoprotective activities. Toxicological results suggest that Xanthium plant extracts are generally safe for use. In the future, additional phytochemical investigations, along with further assessments of the biological profiles and mechanism of action studies of the components of Xanthium species, are to be expected.
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.
Malaria is a major threat to global health and continues to claim lives of many people each year, especially in developing countries. Xanthium strumarium L., is used by traditional health practitioners in the management of malaria fever in North East India. Bioassay guided fractionation of X. strumarium L. extracts, led to the isolation of five compounds from the aerial part and fruit of Xanthium strumarium, namely, stigmasta-5,22-dien-3β-ol (1), xanthinosin (2), stigmasterol-3-O-β-D-glucopyranoside (3), oleic acid (4) and (E)-2, 3-dihydroxypropyl-octadec-9-enoate (5). Antimalarial potential of isolated compounds were evaluated against 3D7 strain of Plasmodium falciparum by schizont maturation inhibition assay method. The structures of isolated compounds were established by HR-MS, NMR experiments and comparison from literature data. Compounds 2 and 3 showed significant antimalarial properties against 3D7 strain of P.falciparum with IC50 value 27.25 and 7.14μM respectively. The antimalarial activities of xanthinosin (2) and stigmasterol-3-O-β-D-glucopyranoside (3) lend credence to the application of X. strumarium against malaria and thus provides new template for development of antimalarial molecules. X. strumarium has also scope for the development of antimalarial phyto-pharmaceutical with five identified compounds with P.falciparum inhibitory activity as per the drugs and cosmetics act of India (1940, amended 31st December 2016).
Effects of methanol extracts of Xanthium strumarium on different cancer cell lines and on the mortality rates of Aedes caspius, Culex pipiens (Diptera: Culicidae) were investigated. Among the cell lines tested, the Jurkat cell line was the most sensitive to the methanol extract and ethyl acetate fraction, with LC50 values reported were 50.18 and 48.73μg/ml respectively. Conversely, methanol extracts were not that toxic to the A549 cell line though the toxicity increased on further purification. The percentage of growth inhibition was dose dependent for the methanol extract and ethyl acetate fraction. The ethyl acetate fraction showed higher toxicity to all cell lines tested when compared to the methanol extract. The results showed that methanol extracts of plant seeds caused 100% mortality of mosquitoes larvae at a concentration of 1000 μg/ml after 24 hr of treatment. The LC50 and LC90 values of X. strumarium were found to be 531.07 and 905.95 μg/ml against Ae. caspius and 502.32 and 867.63 μg/ml against Cx. Pipiens, respectively. From the investigations, it was concluded that the crude extract of X. strumarium showed a weak potential for controlling the larval instars of Ae. caspius and Cx. pipiens. However, on further purification the extract lost the larvicidal activity. The ethyl acetate fraction showed higher toxicity to all cell lines tested when compared to the methanol extract. The ethyl acetate fraction investigated in this study appears to have a weak larvicidal activity but a promising cytotoxic activity. Future studies will include purification and investigation in further detail of the action of X. strumarium on Cancer Cell Lines and mosquitos.
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
Xanthium strumarium L., the main species of the genus Xanthium, is ubiquitously distributed. The aim of this study was to determine the cytotoxic effect of aerial organs of X. strumarium, grown in Cuba, against cancer cell lines and the isolation of compounds potentially responsible for this activity. Initially, an ethanol partitioning procedure yielded the XSE extract that was subsequently fractionated with chloroform resulting in a XSCF fraction. Both, XSE and XSCF fractions exhibited cytotoxic effects on MDA MB-231, MCF7, A549 and CT26 cell lines by using the MTT assay. Above all, the XSCF fraction was more active than XSE. For this reason, XSCF was subsequently fractionated by silica gel chromatography and the active fractions submitted to semi-preparative HPLC for isolation of bioactive compounds. Six sub-fractions (SF1 to SF6) were recovered. Sub-fractions 3 and 6 were the most active on each assayed cell line, while sub-fractions 4 and 5 were only active against A549 and CT26 cell lines. In each case, sub-fraction 6 showed the strongest inhibitory effect. The HPLC-DAD fingerprint of sub-fraction 6 showed a single peak that was identified by GC-MS as (-) spathulenol, a sesquiterpene with reported antitumor activity.
Colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. This is in spite of widespread, effective measures of preventive screening, and also major advances in treatment options. Despite advances in cytotoxic and targeted therapy, resistance to chemotherapy remains one of the greatest challenges in long-term management of incurable metastatic disease and eventually contributes to death as tumors accumulate means of evading treatment. We performed a comprehensive literature search on the data available through PubMed, Medline, Scopus, and the ASCO Annual Symposium abstracts through June 2015 for the purpose of this review. We discuss the current state of knowledge of clinically relevant mechanisms of resistance to cytotoxic and targeted therapies now in use for the treatment of CRC.
Curcumin (Cur) has been extensively studied in several types of malignancies including colorectal cancer (CRC); however its clinical application is greatly affected by low bioavailability. Several strategies to improve the therapeutic response of Cur are being pursued, including its combination with small molecules and drugs. We investigated the therapeutic efficacy of Cur in combination with the small molecule tolfenamic acid (TA) in CRC cell lines. TA has been shown to inhibit the growth of human cancer cells in vitro and in vivo, via targeting the transcription factor specificity protein1 (Sp1) and suppressing survivin expression. CRC cell lines HCT116 and HT29 were treated with TA and/or Cur and cell viability was measured 24-72 hours post-treatment. While both agents caused a steady reduction in cell viability, following a clear dose/ time-dependent response, the combination of TA+Cur showed higher growth inhibition when compared to either single agent. Effects on apoptosis were determined using flow cytometry (JC-1 staining to measure mitochondrial membrane potential), Western blot analysis (c-PARP expression) and caspase 3/7 activity. Reactive oxygen species (ROS) levels were measured by flow cytometry and the translocation of NF-kB into the nucleus was determined using immunofluorescence. Results showed that apoptotic markers and ROS activity were significantly upregulated following combination treatment, when compared to the individual agents. This was accompanied by decreased expression of Sp1, survivin and NF-kB translocation. The combination of TA+Cur was more effective in HCT116 cells than HT29 cells. These results demonstrate that TA may enhance the anti-proliferative efficacy of Cur in CRC cells.
The spindle assembly checkpoint is a safeguard mechanism that coordinates cell-cycle progression during mitosis with the state of chromosome attachment to the mitotic spindle. The checkpoint prevents mitotic cells from exiting mitosis in the presence of unattached or improperly attached chromosomes, thus avoiding whole-chromosome gains or losses and their detrimental effects on cell physiology. Here, I review a considerable body of recent progress in the elucidation of the molecular mechanisms underlying checkpoint signaling, and identify a number of unresolved questions.
The aqueous extraction of the sesquiterpene lactone xanthatin from Xanthium spinosum L. favours the conversion of xanthinin (1) to xanthatin (2) via the loss of acetic acid. The cytotoxic (Hep-G2 and L1210 human cell lines) and antiviral activities of isolated xanthatin are established. This natural compound shows significant cytotoxicity against the Hep-G2 cell line and our experimental results reveal its strong anti-angiogenesis capacity in vitro. The structure of xanthatin is determined by spectroscopic methods and for the first time confirmed by X-ray diffraction.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition, ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines. Ganetespib sensitized CRC cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib, oxaliplatin and 5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation. Ganetespib sensitizes CRC cell lines to the effects of 5FU-based chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC.
Tumor models are critical for our understanding of cancer and the development of cancer therapeutics. Here, we present an integrated map of the genome, transcriptome and immunome of an epithelial mouse tumor, the CT26 colon carcinoma cell line.
We found that Kras is homozygously mutated at p.G12D, Apc and Tp53 are not mutated, and Cdkn2a is homozygously deleted. Proliferation and stem-cell markers, including Top2a, Birc5 (Survivin), Cldn6 and Mki67, are highly expressed while differentiation and top-crypt markers Muc2, Ms4a8a (MS4A8B) and Epcam are not. Myc, Trp53 (tp53), Mdm2, Hif1a, and Nras are highly expressed while Egfr and Flt1 are not. MHC class I but not MHC class II is expressed. Several known cancer-testis antigens are expressed, including Atad2, Cep55, and Pbk. The highest expressed gene is a mutated form of the mouse tumor antigen gp70. Of the 1,688 non-synonymous point variations, 154 are both in expressed genes and in peptides predicted to bind MHC and thus potential targets for immunotherapy development. Based on its molecular signature, we predicted that CT26 is refractory to anti-EGFR mAbs and sensitive to MEK and MET inhibitors, as have been previously reported.vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv CONCLUSIONS: CT26 cells share molecular features with aggressive, undifferentiated, refractory human colorectal carcinoma cells. As CT26 is one of the most extensively used syngeneic mouse tumor models, our data provide a map for the rationale design of mode-of-action studies for pre-clinical evaluation of targeted- and immunotherapies.
Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses prominent anticancer activity. We found that disruption of GSK3β activity was essential for xanthatin to exert its anticancer properties in non-small cell lung cancer (NSCLC), concurrent with preferable suppression of constitutive activation of STAT3. Interestingly, inactivation of the two signals are two mutually exclusive events in xanthatin-induced cell death. Moreover, we surprisingly found that exposure of xanthatin failed to trigger the presumable side effect of canonical Wnt/β-Catenin followed by GSK3β inactivation. We further observed that the downregulation of STAT3 was required for xanthatin to fine-tune the risk. Thus, the discovery of xanthatin, which has ability to simultaneously orchestrate two independent signaling cascades, may have important implications for screening promising drugs in cancer therapies.
The antimicrobial and antioxidant activities and the composition of the essential oil and of the supercritical extracts of Xanthium strumarium were studied. The best yields were observed in the supercritical extracts (SFE). The composition of the extracts obtained by SFE and by hydrodistillation presented little qualitative difference, but they did differ quantitatively. The essential oil contained a high content of β-guaiene (79.6%) while as the major compounds in the supercritical extracts were unidentifiable compound with Kovats Index of 2303 and xanthinin. All the X. strumarium extracts showed strong antimicrobial activity against Staphylococcus aureus, Escherichia coli, Salmonella thyphimurium, Pseudomonas aeruginosa and Clostridium perfringens, however no differences were observed between the extracts. Poor antioxidant activity was found for all the Xanthium strumarium extracts.
Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancer cells, yet little is known about its anticancer mechanism. In this study, we demonstrated that xanthatin had obvious dose-/time-dependent cytotoxicity against the human non-small-cell lung cancer (NSCLC) cell line A549. Flow cytometry analysis showed xanthatin induced cell cycle arrest at G2/M phase. Xanthatin also had pro-apoptotic effects on A549 cells as evidenced by Hoechst 33258 staining and annexin V-FITC staining. Mechanistic data revealed that xanthatin downregulated Chk1, Chk2, and phosphorylation of CDC2, which contributed to the cell cycle arrest. Xathatin also increased total p53 protein levels, decreased Bcl-2/Bax ratio and expression of the downstream factors procaspase-9 and procaspase-3, which triggered the intrinsic apoptosis pathway. Furthermore, xanthatin blocked phosphorylation of NF-κB (p65) and IκBα, which might also contribute to its pro-apoptotic effects on A549 cells. Xanthatin also inhibited TNFα induced NF-κB (p65) translocation. We conclude that xanthatin displays significant antitumor effects through cell cycle arrest and apoptosis induction in A549 cells. These effects were associated with intrinsic apoptosis pathway and disrupted NF-κB signaling. These results suggested that xanthatin may have therapeutic potential against NSCLC.
1
Bioassay-guided fractionation of a CHCl3 extract of the leaves of Xanthium italicum Moretti led to the isolation of four xanthanolides: xanthatin (), 4-epixanthanol ( 2 ), 4-epiisoxanthanol ( 3 ), and 2-hydroxyxanthinosin ( 4 ). Their structures were determined by means of 1D and 2D NMR spectroscopy, including ¹ H- ¹ H COSY, NOESY, HSQC and HMBC experiments, which resulted in complete and unambiguous ¹ H and ¹³ C NMR chemical shift assignments. The isolated compounds 1 - 4 were evaluated for their antiproliferative activities, and were demonstrated to exert significant cell growth inhibitory activity against human cervix adenocarcinoma (HeLa), skin carcinoma (A431), and breast adenocarcinoma (MCF7) cells
Clonogenic assay or colony formation assay is an in vitro cell survival assay based on the ability of a single cell to grow into a colony. The colony is defined to consist of at least 50 cells. The assay essentially tests every cell in the population for its ability to undergo "unlimited" division. Clonogenic assay is the method of choice to determine cell reproductive death after treatment with ionizing radiation, but can also be used to determine the effectiveness of other cytotoxic agents. Only a fraction of seeded cells retains the capacity to produce colonies. Before or after treatment, cells are seeded out in appropriate dilutions to form colonies in 1-3 weeks. Colonies are fixed with glutaraldehyde (6.0% v/v), stained with crystal violet (0.5% w/v) and counted using a stereomicroscope. A method for the analysis of radiation dose-survival curves is included.
This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high‐quality cancer registry data, the basis for planning and implementing evidence‐based cancer control programs, are not available in most low‐ and middle‐income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1‐31. © 2018 American Cancer Society
Ethnopharmacological relevance:
Xanthium strumarium L. is a member of the Asteraceae family popularly used with multiple therapeutic purposes. Whole extracts of this plant have shown anti-mitotic activity in vitro suggesting that some components could induce mitotic arrest in proliferating cells.
Aim of the sudy:
Aim of the present work was to characterize the anti-mitotic properties of the X. strumarium whole extract and to isolate and purify active molecule(s).
Materials and methods:
The capacity of the whole extract to inhibit mitotic progression in mammalian cultured cells was investigated to identify its anti-mitotic activity. Isolation of active component(s) was performed using a bioassay-guided multistep separation procedure in which whole extract was submitted to a progressive process of fractionation and fractions were challenged for their anti-mitotic activity.
Results:
Our results show for the first time that X. strumarium whole extract inhibits assembly of the mitotic spindle and spindle-pole separation, thereby heavily affecting mitosis, impairing the metaphase to anaphase transition and inducing apoptosis. The purification procedure led to a fraction with an anti-mitotic activity comparable to that of the whole extract. Chemical analysis of this fraction showed that its major component was xanthatin.
Conclusions:
The present work shows a new activity of X. strumarium extract, i.e. the alteration of the mitotic apparatus in cultured cells that may be responsible for the anti-proliferative activity of the extract. Anti-mitotic activity is shown to be mainly exerted by xanthatin.
Xanthatin, a xanthanolide sesquiterpene lactone isolated from Xanthium strumarium L. (Asteraceae), has prominent anti-tumor activity. Initial mechanism of action studies suggested xanthatin triggered activation of Wnt/β-catenin. We examined the effects of xanthatin on signaling pathways in A459 lung cancer cells and mouse embryonic fibroblasts to ascertain requirements for xanthatin-induced cell death and tumor growth in xenografts. Genetic inactivation of GSK-3β, but not the related isoform GSK-3α, compromised xanthatin cytotoxicity while inactivation of β-catenin enhanced xanthatin-mediated cell death. These data provide insight into how xanthatin and related molecules could be effectively targeted towards certain tumors.
Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer treatment. In this study, we described a novel VEGFR2 inhibitor, xanthatin, which inhibits tumor angiogenesis and growth. The biochemical profiles of xanthatin were investigated using kinase assay, migration assay, tube formation, Matrigel plug assay, western blot, immunofluorescence and human tumor xenograft model. Xanthatin significantly inhibited growth, migration and tube formation of human umbilical vascular endothelial cell as well as inhibited vascular endothelial growth factor (VEGF)-stimulated angiogenesis. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator. Moreover, xanthatin directly inhibit proliferation of breast cancer cells MDA-MB-231. Oral administration of xanthatin could markedly inhibit human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that xanthatin inhibits angiogenesis and may be a promising anticancer drug candidate.
alpha-Methylene-gamma- and delta-lactones, as well as alpha-methylene-gamma- and delta-lactams, are plant-derived compounds often used in traditional medicine for the treatment of inflammatory diseases. In recent years, the anticancer properties of these compounds and the molecular mechanisms of their action have been studied extensively. In the search for modern anticancer drugs, various synthetic analogs of alpha-methylene-gamma- and delta-lactones and lactams have been synthesized and tested for their cytotoxic activity. In this review, we give a brief description of the occurrence and biological activity of such compounds isolated from plants and their diverse synthetic analogs.
Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1α and NF-κB. Since HSP90 activates HIF-1α and NF-κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1α and NF-κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50 nM for 24 h inhibited EMT (downregulated vimentin and upregulated E-cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF-1α or NF-κB resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our data demonstrate for the first time that inhibition of HSP90 downregulates both HIF-1α and NF-κB leading to inhibition of EMT, motility, and invasiveness in colorectal cancer. © 2014 Wiley Periodicals, Inc.
The natural chalcones and their derivatives exhibit many biological activities, such as anti-inflammatory and antitumoral. However, the precise mechanism(s) of action of benzochalcone derivatives is currently unknown. Here, a set of benzochalcones was synthesized, and the molecular mechanisms underlying inhibition of tumor growth were investigated. Colony forming assays revealed that among tested compounds, 2-hydroxy-4-methoxy-2',3'-benzochalcone (HymnPro) most effectively inhibited the clonogenicity of Capan-1 human pancreatic cancer cells. HymnPro inhibited cell proliferation in several human solid tumor cell lines and suppressed xenografted tumor growth in nude mice. Mechanistically, HymnPro induced cell cycle arrest at the G2/M phase, followed by an increase in apoptotic cell death. These events were associated with the inhibition of tubulin polymerization through binding of HymnPro to tubulin, leading to the formation of abnormal mono- or multipolar mitotic microtubule structures accompanied by spherical arrangement of multinucleated chromosomes. Furthermore, HymnPro activated caspase-2, -9, -3, and -7 and increased the cleavage of poly(ADP-ribose) polymerase (PARP). HymnPro increased the phosphorylation of JNK1/2, Erk1/2, and p38 kinase. Pretreatment with SP600125, U0126, or SB600125 abrogated HymnPro-induced activation of caspase-3, and -7 and the cleavage of PARP, suggesting that MAPK signalings are involved in HymnPro-induced apoptosis. We conclude that a novel HymnPro compound exerts antitumor activity by disrupting microtubule assembly, which leads to mitotic arrest and sequential activation of caspase pathway, resulting in apoptosis.
We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anti-cancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger anti-proliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.
Anti-cancer investigations on Xanthatin mainly focus on in vitro experiments. We herein reported the anti-tumor effects of Xanthatin both in vitro and in vivo. MTS assay results showed that Xanthatin had a remarkable anti-proliferative effect on B16-F10 cells. Moreover, the expression of β-catenin was up-regulated both in vitro and in vivo. Animal studies further revealed that Xanthatin killed the tumor cells around the blood vessels which contributes to reduce microvascular density extremely. All these results indicate that Xanthatin inhibited murine melanoma B16-F10 cell proliferation possibly associated with activation of Wnt/β-catenin pathway and its activity against melanoma tumor might also be relevant to inhibition of angiogenesis.
Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti-metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)-2 and -9 activities and invasion in murine colorectal cancer CT-26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3-kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull-down assay indicated that luteolin non-competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP-2 and -9 activities and invasion in CT-26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT-26 cells. Luteolin also inhibited MMP-9 expression and activity in CT-26-induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti-metastatic agent. Copyright © 2012 John Wiley & Sons, Ltd.
Xanthatin, a natural bioactive compound of sesquiterpene lactones, was isolated and purified from air-dried aerial part of Xanthium sibiricum Patrin ex Widder. In the present study, we demonstrated the significant antiproliferative and proapoptotic effects of xanthatin on human gastric carcinoma MKN-45 cells. MTS assay showed that xanthatin produced obvious cytotoxicity in MKN-45 cells with IC50 values of 18.6, 9.3, and 3.9 µM for 12, 24, and 48 h, respectively. Results of flow cytometry analysis indicated that the antiproliferative activity induced by xanthatin might be executed via G2/M cell cycle arrest and proapoptosis in MKN-45 cells. Western blot analysis elucidated that: a) xanthatin downregulated expression of Chk1 and Chk2 and phosphorylation of CDC2, which are known as key G2/M transition regulators; b) xanthatin increased p53 activation, decreased the bcl-2/bax ratio and the levels of downstream procaspase-9 and procaspase-3, which are key regulators in the intrinsic apoptosis pathway; c) xanthatin blocked phosphorylation of NF-κB (p65 subunit) and of IκBα, which might contribute to its proapoptotic effects on MKN-45 cells. In conclusion, our results suggest that xanthatin may have therapeutic potential against human gastric carcinoma.
The objective of the present work was to evaluate the biological activities of the major bioactive compound, xanthatin, and other compounds from Xanthium strumarium (Asteraceae) leaves. Inhibition of bloodstream forms of Trypanosoma brucei brucei and leukaemia HL-60 cell proliferation was assessed using resazurin as a vital stain. Xanthatin was found to be the major and most active compound against T. b. brucei with an IC(50) value of 2.63 µg/mL and a selectivity index of 20. The possible mode of action of xanthatin was further evaluated. Xanthatin showed antiinflammatory activity by inhibiting both PGE(2) synthesis (24% inhibition) and 5-lipoxygenase activity (92% inhibition) at concentrations of 100 µg/mL and 97 µg/mL, respectively. Xanthatin exhibited weak irreversible inhibition of parasite specific trypanothione reductase. Unlike xanthatin, diminazene aceturate and ethidium bromide showed strong DNA intercalation with IC(50) values of 26.04 µg/mL and 44.70 µg/mL, respectively. Substantial induction of caspase 3/7 activity in MIA PaCa-2 cells was observed after 6 h of treatment with 100 µg/mL of xanthatin. All these data taken together suggest that xanthatin exerts its biological activity by inducing apoptosis and inhibiting both PGE(2) synthesis and 5-lipoxygenase activity thereby avoiding unwanted inflammation commonly observed in diseases such as trypanosomiasis.
The aim of this review is to survey the naturally occurring xanthanes and xanthanolides, their structures, biological activities, structure–activity relationships and synthesis. There has been no comprehensive review of this topic previously. On the basis of 126 references, 112 compounds are summarized.
We describe here the main natural compounds used in cancer therapy and prevention, the historical aspects of their application and pharmacognosy. Two major applications of these compounds are described: as cancer therapeutics and as chemopreventive compounds. Both natural compounds, extracted from plants or animals or produced by microbes (antibiotics), and synthetic compounds, derived from natural prototype structures, are being used. We also focus on the molecular aspects of interactions with their recognized cellular targets, from DNA to microtubules. Some critical aspects of current cancer chemotherapy are also discussed, focusing on genetics and genomics, and the recent revolutionary theory of cancer: aneuploidy as the primum movens of cancer.
Cellular functions induced by cytokine interleukin (IL)-4 and IL-4 signaling through signal transducer and activator of transcription (Stat)6 typify a Th2-type immune response. We investigated the inhibitor effect of the NFkappaB blocker parthenolide in the late-phase, Th2-type immune response. Parthenolide blocked by 90.6 +/- 7.4% the IL-4-induced expression of the endothelial vascular cell adhesion molecule (VCAM)-1, a hallmark of extravasation of very late antigen-4-positive leukocytes. The noncytotoxic concentrations of 10 microM parthenolide left a section of the IL-4 receptor signal transduction intact. Parthenolide did not interfere with the immediate IL-4-induced phosphorylation of endothelial Stat6 on its tyrosine residue Y641 and with tyrosine phosphorylation of the adapter molecule, Jak2-both processes are obligatory for dimerization and nuclear translocation of Stat6. But parthenolide inhibited the Stat6 DNA-binding activity in IL-4-stimulated endothelial cells and inhibited the IL-4-driven activation of a luciferase reporter gene under the control of Stat6-responsive elements (IC(50) 5.11 +/- 0.67 microM). Together, these data suggest an anti-chronic disease profile for the sesquiterpene lactone parthenolide.
Two xanthanolide sesquiterpene lactones, 8- epi-xanthatin (1) and 8- epi-xanthatin epoxide (2), isolated from the leaves of Xanthium strumarium (Compositae), demonstrated a significant inhibition on the proliferation of cultured human tumor cells, i. e., A549 (non-small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nervous system) and HCT-15 (colon) in vitro. They were also found to inhibit the farnesylation process of human lamin-B by farnesyltransferase (FTase), in a dose-dependent manner in vitro (IC 50 value was calculated as 64 and 58 microM, respectively). Due to the relatively high concentrations of 1 and 2 required to obtain an FTase inhibition as compared with those necessary for a cytotoxic effect on tumor cells, it remains unclear whether a relationship between these two activities exists.
Accumulation of mutations and chromosomal aberrations is one of the hallmarks of cancer cells. This enhanced genetic instability is fueled by defects in the genome maintenance mechanisms including DNA repair and cell cycle checkpoint pathways. Here, we discuss the emerging roles of the mammalian Chk1 and Chk2 kinases as key signal transducers within the complex network of genome integrity checkpoints, as candidate tumor suppressors disrupted in sporadic as well as some hereditary malignancies and as potential targets of new anticancer therapies.
Caspases are responsible for crucial aspects of inflammation and immune-cell death that are disrupted in a number of genetic autoimmune and autoinflammatory diseases. The caspase family of proteases can be divided into pro-apoptotic and pro-inflammatory members based on their substrate specificity and participation in separate signalling cascades. However, as discussed here, evidence has emerged over the past few years that a number of the caspases thought to be involved solely in apoptosis also contribute to specific aspects of immune-cell development, activation and differentiation, and can even protect cells from some forms of cell death.
The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.
Xanthatin and xanthinosin from the burs of Xanthium strumarium L. as potential anticancer agents
- I Ramirez-Erosa
- Y Huang
- R A Hickie
- R G Sutherland
- B Barl
Ramirez-Erosa, I., Huang, Y., Hickie, R. A., Sutherland, R. G. and Barl, B. (2007). Xanthatin and
xanthinosin from the burs of Xanthium strumarium L. as potential anticancer agents. Can J
Physiol Pharmacol 85(11): 1160-1172.
Sesquiterpenes and cytotoxicity. Natural Products
- A Sharma
- V K Bajpai
- S Shukla
Sharma, A., Bajpai, V.K., Shukla, S., 2013. Sesquiterpenes and cytotoxicity. Natural
Products. Springer, pp. 3515-3550.
- R Siegel
- J Ma
- Z Zou
- A Jemal
Siegel, R., Ma, J., Zou, Z. and Jemal, A. (2014). Cancer statistics, 2014. CA: a cancer journal for clinicians
64(1): 9-29.
- R L Siegel
- K D Miller
- A Jemal
Siegel, R. L., Miller, K. D. and Jemal, A. (2017). Cancer statistics, 2017. CA: a cancer journal for clinicians
67(1): 7-30.