xanthatin and Colonic-Neoplasms

Xanthatin is a plant-derived bioactive sesquiterpene lactone from the Xanthium strumarium L., and it has been used as a traditional Chinese medicine. Recently, many studies have reported that xanthatin has anticancer activity. However, a comprehensive understanding of the mechanism underlying the antitumor effects of xanthatin is still lacking.. To systematically and comprehensively identify the underlying mechanisms of xanthatin on cancer cells, quantitative proteomic techniques were performed.. Xanthatin induced HT-29 colon cancer cells death was detected by lactate dehydrogenase (LDH) release cell death assay. Differentially abundant proteins in two groups (xanthatin treatment groups and control groups) of human HT-29 colon cancer cells were identified using tandem mass tag (TMT) quantitative proteomic techniques. All the significant differentially abundant proteins were generally characterized by performing hierarchical clustering, Gene Ontology (GO) enrichment analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We chose Western blot analysis to validate the candidate proteins in the proteomics results.. A total of 5637 proteins were identified, of which 397 significantly differentially abundant proteins in the groups were quantified. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses, we found that p53-related signaling played an important role in xanthatin-treated HT-29 colon cancer cells. p53- upregulated modulator of apoptosis (Puma), Sestrin-2 and p14ARF, which were selected from among p53-related signaling proteins, were further validated, and the results were consistent with the tandem mass tag quantitative proteomic results.. We first investigated the molecular mechanism underlying the effects of xanthatin treatment on HT-29 colon cancer cells using tandem mass tag quantitative proteomic methods and provided a global comprehensive understanding of the antitumor effects of xanthatin. However, it is necessary to further confirm the function of the differentially abundant proteins and the potentially associated signaling pathways.

Topics: Colonic Neoplasms; Furans; HT29 Cells; Humans; Proteomics; Signal Transduction; Tumor Suppressor Protein p53

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.

Topics: Cell Line, Tumor; Colonic Neoplasms; Energy Metabolism; Furans; Humans; Signal Transduction; TOR Serine-Threonine Kinases

Colorectal cancer is one of the most common malignancies worldwide and is associated with high mortality rates. We previously reported that Xanthium strumarium L. induces mitotic arrest in proliferating cells, a process mediated by xanthatins.. The aim of this work is to study if xanthatins, isolated from X. strumarium total extract, affect the proliferative capacity of CT26WT colon cancer cells and, in consequence, if tumor growth and proliferation of (lung) metastatic sites can also be arrested in vivo.. This study consisted of both in vitro and in vivo experiments involving the CT26WT cell line and a subcutaneous mouse model of colon cancer. In vitro cell cycle progression, in vivo tumoral growth and anti-metastatic activity were analyzed to investigate whether xanthatins of X. strumarium induce mitotic arrest in proliferating colorectal carcinoma.. X. strumarium antitumor activities are mainly mediated by xanthatins through inhibition of tumor growth and metastasis, inducing mitotic arrest and apoptosis in colon carcinoma cells. These findings further confirm the therapeutic potential of X. strumarium in colorectal cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Furans; Male; Mice, Inbred BALB C; Mitosis; Plant Extracts; Xanthium

The semisynthesis of xanthanolide derivatives is reported from xanthinin and 4-epi-isoxanthanol, two sesquiterpene lactones isolated from the crude chloroformic extract of the leaves of Xanthium macrocarpum DC. (Asteraceae) by liquid/liquid chromatography. In vitro evaluation of their protein farnesyltransferase (PFTase) inhibitory activity has been investigated. In contrast to other biological activities of xanthanolides, PFTase inhibition is not associated with the presence of the potentially toxic alpha-methylene-gamma-lactone function.

Topics: Alkyl and Aryl Transferases; Chloroform; Colonic Neoplasms; Enzyme Assays; Enzyme Inhibitors; HCT116 Cells; Humans; Lactones; Plant Extracts; Plant Leaves; Sesquiterpenes; Solvents; Xanthium