Echinomycin

Echinomycin (quinomycin A) is a peptide antibiotic from the quinoxaline family, which has a DNA bifunctional intercalating activity and an inhibitor of hypoxia-inducible factor (HIF1α). Echinomycin was discovered in 1957 as a potent antitumor agent; however, it was not successful in clinical use due to its low water solubility and short half-life. To revitalize this potent drug, it is important to increase its aqueous solubility and bioavailability. In this study, echinomycin was loaded into PEGylated pH-sensitive liposomes (PEG LippH ) and functionalized with anti-nucleolin aptamer (AptNCL ) for selective targeting and pH-responsive release of echinomycin into cancer cells...

Purpose: N-myc downstream-regulated gene 1 (NDRG1) is expressed in various human tissues and plays a role in regulating cellular proliferation, angiogenesis, and hypoxia sensing. However, the role of NDRG1 in the ovary remains poorly understood. Therefore, we investigated NDRG1 expression and the role of NDRG1 in the human ovary. Methods: Follicular fluid (FF) and luteinized granulosa cells were collected from follicles during oocyte retrieval. KGN cells were cultured with cobalt chloride (CoCl2 , a hypoxia-mimicking agent) and/or echinomycin...

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodelling in hypoxia-induced pulmonary hypertension (HPH). However, its underlying mechanism has not been well elucidated. Connexin 43 (Cx43) plays crucial roles in vascular smooth muscle cell proliferation in various cardiovascular diseases. Here, the male Sprague-Dawley (SD) rats were exposed to hypoxia (10% O2 ) for 21 days to induce rat HPH model. PASMCs were treated with CoCl2 (200 µM) for 24 h to establish the HPH cell model...

A biologically active microbial strain, designated as LS462, was isolated from a soil sample collected from Yaoli Virgin Forest of Jiangxi Province, China. The strain was able to produce a high yield of echinomycin (172 mg/L) even under non-optimized culture conditions and proposed to serve as a promising source of echinomycin. In this study, echinomycin exhibited strong anti-Mycobacterium tuberculosis H37Rv activity and synergistic antifungal effect with a greatly reduced dosage of posaconazole on Candida albicans SC5314...

OBJECTIVE: To investigate the relationship between hypoxia inducible factor 1 (HIF1α) and Wilms' tumor 1associating protein (WTAP) expression level in t(8;21) acute myeloid leukemia cells. METHODS: The t(8;21) acute myeloid leukemia cell lines, including SKNO-1 and Kasumi-1 were treated by Echinomycin for 24 h, RT-qPCR and Western blot were used to detect the expression levels of WTAP mRNA and the protein. The CoCl 2 was used to induce the hypoxia of the cells for 24 h, the expression levels of HIF1α, WTAP protein were detected by Western blot...

Methane emissions from enteric fermentation in the ruminant digestive system generated by methanogenic archaea are a significant contributor to anthropogenic greenhouse gas emissions. Additionally, methane produced as an end-product of enteric fermentation is an energy loss from digested feed. To control the methane emissions from ruminants, extensive research in the last decades has been focused on developing viable enteric methane mitigation practices, particularly, using methanogen-specific inhibitors. We report here the utilization of two known inhibitors of methanogenic archaea, neomycin and chloroform, together with a recently identified inhibitor, echinomycin, to produce resistant mutants of Methanococcus maripaludis S2 and S0001...

Oncogenic Ras mutations are highly prevalent in hematopoietic malignancies. However, it is difficult to directly target oncogenic RAS proteins for therapeutic intervention. We have developed a Drosophila acute myeloid leukemia model induced by human KRASG12V, which exhibits a dramatic increase in myeloid-like leukemia cells. We performed both genetic and drug screens using this model. The genetic screen identified 24 candidate genes able to attenuate the oncogenic RAS-induced phenotype, including two key hypoxia pathway genes HIF1A and ARNT (HIF1B)...

Quinoxaline (C8H6N2), commonly called 1,4-diazanaphthalene, 1,4-benzodiazine, or benzopyrazine, is a very potent nitrogenous heterocyclic moiety consisting of a benzene ring fused with the pyrazine ring. A number of different methods for the synthesis of quinoxaline derivatives have been reported in the literature, but the most effective method, commonly used for the synthesis of quinoxaline analogues involves the condensation of substituted o-phenylenediamines with 1, 2- dicarbonyl compounds in the presence of different catalyst(s)...

The increase of oxidative stress is one of the important characteristics of mammalian luteal regression. Previous investigations have revealed the essential role of reactive oxygen species (ROS) in luteal cell death during luteolysis, while it is unknown how ROS is regulated in this process. Considering the decrease of blood flow and increase of PGF2 α during luteolysis, we hypothesized that the HIF-1 α pathway may be involved in the regulation of ROS in the luteal cell of the late corpus luteum (CL). Here, by using a pseudopregnant rat model, we showed that the level of both HIF-1 α and its downstream BNIP3 was increased during luteal regression...

BACKGROUND: Glioblastoma multiforme (GBM), a lethal brain tumor, remains the most daunting challenge in cancer therapy. Overexpression and constitutive activation of PDGFs and PDGFRα are observed in most GBM; however, available inhibitors targeting isolated signaling pathways are minimally effective. Therefore, better understanding of crucial mechanisms underlying GBM is needed for developing more effective targeted therapies. METHODS: Target genes controlled by HIF1α in GBM were identified by analysis of TCGA database and by RNA-sequencing of GBM cells with HIF1α knockout by sgRNA-Cas9 method...

Hypoxia increases fetal hepatic insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon (Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR-mediated IGFBP-1 hyperphosphorylation in response to hypoxia requires hypoxia-inducible factor-1α (HIF-1α) and regulated in development and DNA-damage responses-1 (REDD-1) signaling...

Intracellular free zinc ([Zn2+ ]i ) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn2+ ]i is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn2+ have been identified, proteins that are involved in Zn2+ supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn2+ transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn2+ ]i accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn2+ ]i ...

For patients with anaplastic Wilms tumor (WiT), metastasis and recurrence are common, and prognosis is generally poor. Novel therapies are needed to improve outcomes for patients with this high-risk WiT. A potential contributor to WiT development is constitutive activation of AKT by insulin-like growth factor 1 (IGF1) and its receptor (IGF1R) signaling pathway, but the complete underlying mechanism remains unclear. Here, we demonstrate that the hypoxia-inducible factor 1α (HIF-1α)-IGF binding protein 2 (IGFBP2) axis and the tumor-specific IGF1A are key players for constitutive activation of IGF1-AKT signaling leading to the tumor malignancy...

Indonesia is one of the most biodiverse countries in the world and a promising resource for novel natural compound producers. Actinomycetes produce about two thirds of all clinically used antibiotics. Thus, exploiting Indonesia's microbial diversity for actinomycetes may lead to the discovery of novel antibiotics. A total of 422 actinomycete strains were isolated from three different unique areas in Indonesia and tested for their antimicrobial activity. Nine potent bioactive strains were prioritized for further drug screening approaches...

BACKGROUND: Echinomycin (EKN), an inhibitor of hypoxia-inducible factor (HIF)-1 DNA-binding activity, has been implied as a possible therapeutic agent in ischemic diseases. Here, we assess EKN in hypoxia-driven responses in vitro using human primary adult retinal pigment epithelium cells (aRPE) and retinal endothelial cells (hREC), and in vivo using the laser-induced mouse choroidal neovascularization (CNV) model. METHODS: Effects of EKN on hypoxia-mediated pathways in aRPE were analyzed by Western blotting for HIF-1α protein, quantitative PCR of HIF-target genes, and proteome array for soluble angiogenic factors...

MYC and HIF1α are among the most important oncoproteins whose pharmacologic inhibition has been challenging for the diverse mechanisms driving their abnormal expression and because of the challenge in blocking protein-DNA interactions. Surprisingly, we found that MYC and HIF1α proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the β-TrCP- or VHL-dependent mechanisms. The degradation is induced in a variety of cancer types, including those with mutations in the p53 tumor and LKB tumor suppressors and the KRAS oncogene...

Owing to the avascular structure of the ovarian follicle, proliferation of granulosa cells (GCs) and development of follicles occur under hypoxia, which is obviously different from the cell survival requirements of most mammalian cells. We hypothesized that autophagy may exert an inhibitory effect on GC apoptosis. To decipher the underlying mechanism, we constructed a rat follicular development model using pregnant mare serum gonadotropin and a cell culture experiment in hypoxic conditions (3% O2 ). The present results showed that the autophagy level was obviously increased and was accompanied by the concomitant elevation of hypoxia inducible factor (HIF)-1α and BNIP3 (Bcl-2/adenovirus E1B 19kDa-interacting protein 3) in GCs during follicular development...

DNA replication is an exceptional point of therapeutic intervention for many cancer types and several small molecules targeting DNA have been developed into clinically used antitumor agents. Many of these molecules are naturally occurring metabolites from plants and microorganisms, such as the widely used chemotherapeutic doxorubicin. While natural product sources contain a vast number of DNA binding small molecules, isolating and identifying these molecules is challenging. Typical screening campaigns utilize time-consuming bioactivity-guided fractionation approaches, which use sequential rounds of cell-based assays to guide the isolation of active compounds...

BACKGROUND: We previously demonstrated that heme oxygenase-1 (HO-1) induction may contribute to a protective response against photodynamic therapy (PDT) using talaporfin sodium (TS) in rat malignant meningioma KMY-J cells. In the present study, we examined the mechanism of HO-1 induction by PDT with TS (TS-PDT) in KMY-J cells. METHODS: KMY-J cells were incubated with 25 µM TS for 2 h and then exposed to 664 nm diode laser irradiation at 1 J/cm2 . The gene and protein expression levels of HO-1 and hypoxia-inducible factor-1α (HIF-1α) were determined by real-time RT-PCR and western blot analysis, respectively...

Nonribosomal peptides (NRPs) are natural products that are biosynthesized by large multi-enzyme assembly lines called nonribosomal peptide synthetases (NRPSs). We have previously discovered that backbone or side chain methylation of NRP residues is carried out by an interrupted adenylation (A) domain that contains an internal methyltransferase (M) domain, while maintaining a monolithic AMA fold of the bifunctional enzyme. A key question that has remained unanswered is at which step of the assembly line mechanism the methylation by these embedded M domains takes place...