Browse
Submit Data
Databases
API
Help

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Auranofin, Et3PAuCl, and Et3PAuI Are Highly Cytotoxic on Colorectal Cancer Cells: A Chemical and Biological Study.

ABSTRACT: The solution behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, in vivo acute toxicity experiments for Et3PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for Et3PAuI and Et3PAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacological action, suggesting that the tuning of some relevant chemical properties such as lipophilicity could be exploited to improve bioavailability, with no loss of the pharmacological effects.

SUBMITTER: Marzo T

PROVIDER: S-EPMC5641946 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells.

Project description:Malignant melanoma is the most dangerous type of skin cancer. Although recent progress in treatment has been achieved, lack of response, drug resistance and relapse remain major problems. The tumor suppressor p53 is rarely mutated in melanoma, yet it is inactive in the majority of cases due to dysregulation of upstream pathways. Thus, we screened for compounds that can activate p53 in melanoma cells. Here we describe effects of the small molecule MJ25 (2-{[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]thio}-1,3-benzoxazole), which increased the level of p53-dependent transactivation both as a single agent and in combination with nutlin-3. Furthermore, MJ25 showed potent cytotoxicity towards melanoma cell lines, whilst having weaker effects against human normal cells. MJ25 was also identified in an independent screen as an inhibitor of thioredoxin reductase 1 (TrxR1), an important selenoenzyme in the control of oxidative stress and redox regulation. The well-characterized TrxR inhibitor auranofin, which is FDA-approved and currently in clinical trials against leukemia and a number of solid cancers, displayed effects comparable with MJ25 on cells and led to eradication of cultured melanoma cells at low micromolar concentrations. In conclusion, auranofin, MJ25 or other inhibitors of TrxR1 should be evaluated as candidate compounds or leads for targeted therapy of malignant melanoma.

| S-EPMC4599284 | biostudies-literature

Expansion of highly cytotoxic human natural killer cells for cancer cell therapy.

Project description:Infusions of natural killer (NK) cells are an emerging tool for cancer immunotherapy. The development of clinically applicable methods to produce large numbers of fully functional NK cells is a critical step to maximize the potential of this approach. We determined the capacity of the leukemia cell line K562 modified to express a membrane-bound form of interleukin (IL)-15 and 41BB ligand (K562-mb15-41BBL) to generate human NK cells with enhanced cytotoxicity. Seven-day coculture with irradiated K562-mb15-41BBL induced a median 21.6-fold expansion of CD56(+)CD3(-) NK cells from peripheral blood (range, 5.1- to 86.6-fold; n = 50), which was considerably superior to that produced by stimulation with IL-2, IL-12, IL-15, and/or IL-21 and caused no proliferation of CD3(+) lymphocytes. Similar expansions could also be obtained from the peripheral blood of patients with acute leukemia undergoing therapy (n = 11). Comparisons of the gene expression profiles of the expanded NK cells and their unstimulated or IL-2-stimulated counterparts showed marked differences. The expanded NK cells were significantly more potent than unstimulated or IL-2-stimulated NK cells against acute myeloid leukemia cells in vitro. They could be detected for >1 month when injected into immunodeficient mice and could eradicate leukemia in murine models of acute myeloid leukemia. We therefore adapted the K562-mb15-41BBL stimulation method to large-scale clinical-grade conditions, generating large numbers of highly cytotoxic NK cells. The results that we report here provide rationale and practical platform for clinical testing of expanded and activated NK cells for cell therapy of cancer.

| S-EPMC2716664 | biostudies-literature

Auranofin and its analogs as prospective agents for the treatment of colorectal cancer.

Project description:Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought. Platinum drugs, oxaliplatin in particular, were reported to produce some significant benefit in CRC treatment, triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs. Within this frame, gold compounds and, specifically, the established antiarthritic drug auranofin with its analogs, form a novel group of promising anticancer agents. Owing to its innovative mechanism of action and its favorable pharmacological profile, auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment, capable of overcoming resistance to platinum drugs. Some encouraging results in this direction have already been obtained. A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations. The perspectives of the research in this field are outlined.

| S-EPMC8992591 | biostudies-literature

Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement.

Project description:Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15?years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3?months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.

| S-EPMC3719916 | biostudies-literature

Redox proteome analysis of auranofin exposed ovarian cancer cells (A2780).

Project description:The effects of Auranofin (AF) on protein expression and protein oxidation in A2780 cancer cells were investigated through a strategy based on simultaneous expression proteomics and redox proteomics determinations. Bioinformatics analysis of the proteomics data supports the view that the most critical cellular changes elicited by AF treatment consist of thioredoxin reductase inhibition, alteration of the cell redox state, impairment of the mitochondrial functions, metabolic changes associated with conversion to a glycolytic phenotype, induction of ER stress. The occurrence of the above cellular changes was extensively validated by performing direct biochemical assays. Our data are consistent with the concept that AF produces its effects through a multitarget mechanism that mainly affects the redox metabolism and the mitochondrial functions and results into severe ER stress. Results are discussed in the context of the current mechanistic knowledge existing on AF.

| S-EPMC8966199 | biostudies-literature

Hispanic Colorectal Cancer Study

Project description:Hispanic Colorectal Cancer Study

| PRJNA339338 | ENA

Cyto-biological effects of microRNA-424-5p on human colorectal cancer cells.

Project description:MicroRNA (miR)-424-5p is overexpressed in colorectal cancer (CRC); however, its role, clinical significance and underlying molecular mechanism have remained to be fully elucidated. The aim of the present study was to investigate the roles of miR-424-5p in CRC and the underlying mechanisms. It was demonstrated that miR-424-5p is overexpressed in CRC, based on bioinformatics analysis using The Cancer Genome Atlas TCGA and analysis of tissue samples from patients with CRC from The First Hospital of Hebei Medical University, and the expression of miR-424-5p was associated with the depth of invasion and Dukes' staging. In CRC cells, the oncogenic roles of miR-424-5p were also verified by Cell Counting Kit-8, wound healing and Transwell assays. To identify target genes, all transcripts were compared between miR-424-5p mimic-transfected SW480 cells and mimic control cells by transcriptome sequencing. Subsequently, the differentially expressed genes (DEGs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The DEGs were revealed to be significantly enriched in the GO terms 'serine hydrolase activity,' 'serine-type peptidase activity' and 'serine-type endopeptidase activity'. KEGG signaling pathway analysis indicated that the DEGs were significantly enriched in 'endocytosis', 'regulation of actin cytoskeleton', 'Wnt signaling pathway' and 'ubiquitin-mediated proteolysis signaling pathway'. These results suggested that miR-424-5p is a potential target in the treatment of CRC.

| S-EPMC7448566 | biostudies-literature

circZC3HAV1 Regulates TBC1D9 to Affect the Biological Behavior of Colorectal Cancer Cells.

Project description:BackgroundColorectal cancer (CRC) is one of the most frequently diagnosed cancers all over the world, which accounts for a large proportion of cancer-associated deaths. The regulatory function of circular RNAs (circRNAs) has been affirmed in diverse cancers. circ_0082628, named circRNA zinc finger CCCH-type containing antiviral 1 (circZC3HAV1), has been discovered to be significantly downregulated in CRC tissues. Nevertheless, the function and mechanism of circZC3HAV1 in CRC remain unclear.PurposeWe targeted at studying the specific role and mechanism of circZC3HAV1 in CRC cells.MethodsThe expression of the genes was detected by quantitative real-time polymerase chain reaction (qPCR). The binding relationship among different genes was verified by mechanism assays. Functional assays were carried out to reveal the role of different RNAs in CRC cell malignant behaviors.ResultscircZC3HAV1 was significantly downregulated in CRC cells. circZC3HAV1 overexpression hampered CRC cell migratory and invasive abilities. As for the mechanism, circZC3HAV1 competitively bound with microRNA-146b-3p (miR-146b-3p) to enhance the expression of TBC1 domain family member 9 (TBC1D9). Rescue assays demonstrated circZC3HAV1 sponged miR-146b-3p and upregulated TBC1D9 to restrict migration and invasion of CRC cells.ConclusioncircZC3HAV1 could upregulate TBC1D9 via absorbing miR-146b-3p, consequently inhibiting migratory and invasive capabilities of CRC cells.

| S-EPMC9508460 | biostudies-literature

Methylated Xanthones from the Rootlets of Metaxya rostrata Display Cytotoxic Activity in Colorectal Cancer Cells.

Project description:The tree fern Metaxya rostrata (Kunth) C. Presl is common in the rainforests of Central and South America, where suspensions of the dried rhizome are traditionally used to treat intestinal diseases. Two compounds from this plant, 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB), have been shown to be biologically highly active against colorectal cancer (CRC) cells in previous studies. The current investigation resulted in the isolation of the previously undescribed methylated xanthones 2-deprenyl-6-O-methyl-7-hydroxy-rheediaxanthone B, 2-deprenyl-5-O-methyl-7-methoxy-rheediaxanthone B, 2-deprenyl-5-O-methyl- 7-hydroxy-rheediaxanthone B and 2-deprenyl-7-methoxy-rheediaxanthone B. All compounds were isolated by column chromatography, structures were elucidated by one- and two-dimensional NMR-experiments and the identities of the compounds were confirmed by LC-HRMS. In logarithmically growing SW480 CRC cell cultures, cytotoxicity by neutral red uptake and MTT assays as well as caspase activation was analyzed. Cellular targets were examined by Western blot, and topoisomerase I (topo I) inhibition potential was tested. Comparing the structure-activity relationship with XB and OH-XB, the monomethylated derivatives showed qualitatively similar effects/mechanisms to their nonmethylated analogues, while dimethylation almost abolished the activity. Inhibition of topo I was dependent on the presence of an unmethylated 7-OH group.

| S-EPMC7582535 | biostudies-literature

EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells.

Project description:Enhancer of zeste homolog 2 (EZH2) has been emerged as novel anticancer target. Various EZH2 small-molecule inhibitors have been developed in recent years. A major class of EZH2 inhibitors are S-adenosyl-L-methionine (SAM)-competitive inhibitors, such as EPZ005687, EI1, GSK126, UNC1999 and GSK343. Autophagy, a physiological process of self-digestion, is involved in the turnover of proteins or intracellular organelles. It can serve as cytoprotective or cytotoxic function in cancer. Our previous study has found that UNC1999 and GSK343 are potent autophagy inducers. In this study, the underlying molecular mechanisms were further investigated. Our results showed that UNC1999 and GSK343 transcriptionally upregulated autophagy of human colorectal cancer (CRC) cells through inducing LC3B gene expression. Besides, UNC1999/GSK343-induced autophagy was partially dependent on ATG7 but independent to EZH2 inhibition. Microarray and PCR array analyses identified that UNC1999 and GSK343 also induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UNC1999/GSK343-induced ER stress/UPR contributed to the survival of cancer cells, which was opposite to UNC1999/GSK343-induced autophagy that promoted cell death.

| S-EPMC5004071 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data