Echinomycin

The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options...

Cadmium (Cd) is an environmental risk factor of cardiovascular diseases. Researchers have found that Cd exposure causes energy metabolic disorders in the heart decades ago. However, the underlying molecular mechanisms are still elusive. In this study, male C57BL/6 J mice were exposed to cadmium chloride (CdCl2 ) through drinking water for 4 weeks. We found that exposure to CdCl2 increased glucose uptake and utilization, and disrupted normal metabolisms in the heart. In vitro studies showed that CdCl2 specifically increased endothelial glucose uptake without affecting cardiomyocytic glucose uptake and endothelial fatty acid uptake...

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3...

High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression...

Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer's disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression...

Echinomycin is a natural product DNA bisintercalator antibiotic. The echinomycin biosynthetic gene cluster in Streptomyces lasalocidi includes a gene encoding the self-resistance protein Ecm16. Here, we present the 2.0 Å resolution crystal structure of Ecm16 bound to adenosine diphosphate. The structure of Ecm16 closely resembles that of UvrA, the DNA damage sensor component of the prokaryotic nucleotide excision repair system, but Ecm16 lacks the UvrB-binding domain and its associated zinc-binding module found in UvrA...

Cancer is a set of complex diseases, being one of the leading causes of death worldwide. Despite a lot of research on the molecular pathways and effective treatments, there are still huge gaps. Indeed, the development of new anti-cancer drugs is a complex process. To face this problem, drug repurposing is being increasingly applied. This approach aims to identify new indications for already approved drugs. In this regard, statins (clinically used for reducing cholesterol levels) are reported to induce anti-cancer effects, particularly by inducing apoptosis and altering the tumor microenvironment...

The mechanisms underlying pre-labor uterine quiescence and uterine atony during overdistention are unclear. TREK1 (a two-pore domain potassium channel) and hypoxia-inducible factor-1α (HIF-1α) are activated by mechanical stretch, and their expression is upregulated by decreased uterine contractility. HIF-1α is a nuclear factor which regulates numerous target proteins, but whether it regulates TREK1 during uterine stretch to cause uterine quiescence and/or atony is unclear. We investigated uterine contractility at different gestational stages in rats, as well as in non-pregnant uteri, which were induced by prolonged stretching and hypoxia...

Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches...

BACKGROUND: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM patients have a significantly higher rate of cesarean section and postpartum hemorrhage, suggesting changes in uterine contractility. TWIK-1-related potassium channel (TREK1) expressed in the pregnant uterus and its role in uterine contraction. In this study, we examined the expression of HIF-1α and TREK1 proteins in GDM uterine and investigated whether high glucose levels are involved in the regulation of human uterine smooth muscle cells (HUSMCs) contraction through TREK1, and verified the role of HIF-1α in this process...

BACKGROUND: Canine mammary gland tumors can be used as predictive models for human breast cancer. There are several types of microRNAs common in human breast cancer and canine mammary gland tumors. The functions of microRNAs in canine mammary gland tumors are not well understood. METHODS: We compared the characterization of microRNA expression in two-dimensional and three-dimensional canine mammary gland tumor cell models. We evaluated the differences between two- and three-dimensional cultured canine mammary gland tumor SNP cells by assessing microRNA expression levels, morphology, drug sensitivity, and hypoxia...

BACKGROUND: New antibiotics are urgently needed in clinical treatment of superdrug-resistant bacteria. Nonribosomal peptides (NRPs) are a major source of antibiotics because they exhibit structural diversity, and unique antibacterial mechanisms and resistance. Analysis of gene clusters of S. agglomeratus 5-1-3 showed that Clusters 3, 6, 12, 21, and 28 were used to synthesize NRPs. Here, we examined secondary metabolites of S. agglomeratus 5-1-3 isolated from soils in the Qinghai-Tibet Plateau, China, for NRPs with antibacterial activity...

OBJECTIVE: Sepsis Associated Encephalopathy (SAE) is a common complication in critically ill patients and perioperative period, but its pathogenesis is still unclear. This study aimed to explore the effect of the HIF-1α (hypoxia-inducible factor-1α)/BNIP3L (Bcl-2/adenovirus E1B 19-kDa interaction protein) signaling pathway on SAE. METHODS: C57BL/6J male mice were divided into four groups, using a random number table method: control group, sham group, sepsis group, sepsis+HIF-1α activity inhibitor (echinomycin) group...

Chronic myeloid leukemia (CML) has a markedly improved prognosis with the use of breakpoint cluster region-abelson 1 (BCR-ABL1) tyrosine kinase inhibitors (BCR-ABL1 TKIs). However, approximately 40% of patients are resistant or intolerant to BCR-ABL1 TKIs. Hypoxia inducible factor 1α (HIF-1α) is a hypoxia response factor that has been reported to be highly expressed in CML patients, making it a candidate target molecule for the therapy of CML as well as BCR-ABL1 TKI-resistant CML. In this study, we examined whether HIF-1α inhibitors induce cell death in CML cells and BCR-ABL1 TKI-resistant CML cells...

Naked mole-rats (NMRs) (Heterocephalus glaber) are highly social and subterranean rodents with large communal colonies in burrows containing low oxygen levels. The inhibition of severe hypoxic conditions is of particular interest to this study. To understand the mechanisms that facilitate neuronal preservation during hypoxia, we investigated the proteins regulating hypoxia tolerance in NMR hippocampal neurons. Caveolin-1 (Cav-1), a transmembrane scaffolding protein, confers prosurvival signalling in the central nervous system...

Introduction: Oxidative phosphorylation is an essential feature of Animalian life. Multiple adaptations have developed to protect against hypoxia, including hypoxia-inducible-factors (HIFs). The major role of HIFs may be in protecting against oxidative stress, not the preservation of high-energy phosphates. The precise mechanism(s) of HIF protection is not completely understood. Materials and Methods: To better understand the role of hypoxia-inducible-factor-1, we exposed heart/myocardium cells (H9c2) to both normoxia and hypoxia, as well as cobalt chloride (prolyl hydroxylase inhibitor), echniomycin (HIF inhibitor), A2P (anti-oxidant), and small interfering RNA to beclin-1...

The use of multiple drugs simultaneously targeting DNA is a promising strategy in cancer therapy for potentially overcoming single drug resistance. In support of this concept, we report that a combination of actinomycin D (ActD) and echinomycin (Echi), can interact in novel ways with native and mismatched DNA sequences, distinct from the structural effects produced by either drug alone. Changes in the former with GpC and CpG steps separated by a A:G or G:A mismatch or in a native DNA with canonical G:C and C:G base pairs, result in significant asymmetric backbone twists through staggered intercalation and base pair modulations...

The majority of base pairs in double-stranded DNA exist in the canonical Watson-Crick geometry. However, they can also adopt alternate Hoogsteen conformations in various complexes of DNA with proteins and small molecules, which are key for biological function and mechanism. While detection of Hoogsteen base pairs in large DNA complexes and assemblies poses considerable challenges for traditional structural biology techniques, we show here that multidimensional dynamic nuclear polarization-enhanced solid-state NMR can serve as a unique spectroscopic tool for observing and distinguishing Watson-Crick and Hoogsteen base pairs in a broad range of DNA systems based on characteristic NMR chemical shifts and internuclear dipolar couplings...

OBJECTIVE: To investigate effects of physiological hypoxic conditions on suspension and adherence of embryoid bodies (EBs) during differentiation of human induced pluripotent stem cells (hiPSCs) and explore the underlying mechanisms. METHODS: EBs in suspension culture were divided into normoxic (21% O2 ) and hypoxic (5% O2 ) groups, and those in adherent culture were divided into normoxic, hypoxic and hypoxia + HIF-1 α inhibitor (echinomycin) groups. After characterization of the pluripotency with immunofluorescence assay, the hiPSCs were digested and suspended under normoxic and hypoxic conditions for 5 days, and the formation and morphological changes of the EBs were observed microscopically; the expressions of the markers genes of the 3 germ layers in the EBs were detected...

OBJECTIVE: To investigate the antitumor effects of the selective hypoxia-inducible factor-1 (HIF-1) inhibitors echinomycin and PX-478 on uterine fibroids. DESIGN: Experimental study using in vitro primary culture systems and an in vivo mouse xenograft model. SETTING: Academic university center. PATIENT(S): Women with uterine fibroids who underwent hysterectomy or myomectomy. INTERVENTION(S): Administration of the selective HIF-1 inhibitors echinomycin and PX-478 to the media of the primary cultured uterine fibroid cells and to nonobese diabetic/severe combined immunodeficient mice bearing fibroid xenografts consisting of the primary cultured fibroid cells and type Ⅰ collagen gels beneath the kidney capsule...