Search Results (183)

The stomach has been a highly conserved organ throughout vertebrate evolution; however, there are now over 20 lineages composed of monotremes, lungfish and teleost fish displaying a secondary loss of stomach function and morphology. This “agastric phenotype” has evolved convergently and is typified by a loss of gastric glands and gastric acid secretion and a near-to-complete loss of storage capacity of the stomach. All agastric species have lost the genes for gastric enzymes (Pga and Pgc) and proton pump subunits (Atp4a and Atp4b), and gastrin (Gast) has been lost in monotremes. As a key gastric hormone, the conservation of gastrin has not yet been investigated in the lungfish or agastric teleosts, and it is unclear how the loss of gastrin affects the evolution and selection of the native receptor (Cckbr), gastrin-releasing peptide (Grp) and gastrin-releasing peptide receptor (Grpr) in vertebrates. Furthermore, there are still many genes implicated in gastric development and function which have yet to be associated with the agastric phenotype. We analysed the evolution, selection and conservation of the gastrin pathway and a novel gastric gene repertoire (Gkn1, Gkn2, Tff1, Tff2, Vsig1 and Anxa10) to determine the correlation with the agastric phenotype. We found that the loss of gastrin or its associated genes does not correlate with the agastric phenotype, and their conservation is due to multiple pleiotropic roles throughout vertebrate evolution. We found a loss of the gastric gene repertoire in the agastric phenotype, except in the echidna, which retained several genes (Gkn1, Tff2 and Vsig1). Our findings suggest that the gastrin physiological pathway evolved differently in pleiotropic roles throughout vertebrate evolution and support the convergent evolution of the agastric phenotype through shared independent gene-loss events. Full article

The enteroendocrine system of the gastrointestinal (GI) tract is the largest endocrine organ in the human body, playing a central role in the regulation of hunger, satiety, digestion, and energy homeostasis. Numerous factors—including dietary components, physical activity, and the gut microbiota—affect the secretion of GI hormones. This study aims to analyze how these factors modulate enteroendocrine function and influence systemic metabolic regulation. This review synthesizes the current scientific literature on the physiology and distribution of enteroendocrine cells and mechanisms of hormone secretion in response to macronutrients, physical activity, and microbial metabolites. Special attention is given to the interactions between gut-derived signals and central nervous system pathways involved in appetite control. Different GI hormones are secreted in specific regions of the digestive tract in response to meal composition and timing. Macronutrients, particularly during absorption, stimulate hormone release, while physical activity influences hormone concentrations, decreasing ghrelin and increasing GLP-1, PYY, and leptin levels. The gut microbiota, through fermentation and metabolite production (e.g., SCFAs and bile acids), modulates enteroendocrine activity. Species such as Akkermansia muciniphila are associated with improved gut barrier integrity and enhanced GLP-1 secretion. These combined effects contribute to appetite regulation and energy balance. Diet composition, physical activity, and gut microbiota are key modulators of gastrointestinal hormone secretion. Their interplay significantly affects appetite regulation and metabolic health. A better understanding of these relationships may support the development of personalized strategies for managing obesity and related disorders. Full article

Background/Objectives: Gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and might be used as a theranostics target. The expression of GRPR strongly correlates with estrogen receptor (ER) expression. Visualization of GRPR-expressing breast tumors might help to select the optimal treatment. Developing GRPR-specific probes for SPECT would permit imaging-guided therapy in regions with restricted access to PET facilities. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the [^99mTc]Tc-DB8 GRPR-antagonistic peptide. We also addressed the important issue of finding the optimal injected peptide mass. Methods: Fifteen female patients with ER-positive primary breast cancer were enrolled and divided into three cohorts receiving [^99mTc]Tc-DB8 (corresponding to three distinct doses of 40, 80, or 120 µg DB8) comprising five patients each. Additionally, four patients with ER-negative primary tumors were injected with 80 µg [^99mTc]Tc-DB8. The injected activity was 360 ± 70 MBq. Planar scintigraphy was performed after 2, 4, 6, and 24 h, and SPECT/CT scans followed planar imaging 2, 4, and 6 h after injection. Results: No adverse events were associated with [^99mTc]Tc-DB8 injections. The effective dose was 0.009–0.014 mSv/MBq. Primary tumors and all known lymph node metastases were visualized irrespective of injected peptide mass. The highest uptake in the ER-positive tumors was 2 h after injection of [^99mTc]Tc-DB8 at a 80 µg DB8 dose (SUV_max 5.3 ± 1.2). Injection of [^99mTc]Tc-DB8 with 80 µg DB8 provided significantly (p < 0.01) higher uptake in primary ER-positive breast cancer lesions than injection with 40 µg DB8 (SUV_max 2.0 ± 0.3) or 120 µg (SUV_max 3.2 ± 1.4). Tumor-to-contralateral breast ratio after injection of 80 μg was also significantly (p < 0.01, ANOVA test) higher than ratios after injection of other peptide masses. The uptake in ER-negative lesions was significantly lower (SUV_max 2.0 ± 0.3) than in ER-positive tumors. Conclusions: Imaging using [^99mTc]Tc-DB8 is safe, tolerable, and associated with low absorbed doses. The tumor uptake is dependent on the injected peptide mass. The injection of an optimal mass (80 µg) provides the highest uptake in ER-positive tumors. At optimal dosing, the uptake was significantly higher in ER-positive than in ER-negative lesions. Full article

Objective: To investigate the effects of oat fiber on animal constipation and elucidate its underlying mechanisms. Methods: Male BALB/c mice were randomly allocated into five groups: control group (CON), model control group (MODEL), low dose group (LOW), middle dose group (MIDDLE), high dose group (HIGH). Constipation was induced in the mice by intragastric administration of loperamide. Subsequently, the mice (except those in the CON and MODEL groups) were administered oat fiber intragastrically for 21 consecutive days. Results: Compared with the MODEL group, oat fiber significantly increased the number of fecal pellets, fecal wet weight, and fecal water content (p < 0.05), shortened the time to first black stool excretion (p < 0.05), and enhanced the small intestinal propulsion rate in constipated mice. Additionally, oat fiber significantly upregulated motilin (MTL) and gastrin (GAS) levels (p < 0.05), while downregulating vasoactive intestinal peptide (VIP) and somatostatin (SS) levels (p < 0.05). It also significantly reduced the transcription level of Aquaporin 8 (AQP8) (p < 0.05), effectively alleviating intestinal mucosal injury and immune inflammation. The relative expression levels of TNF-α and IL-1β were significantly decreased in the oat fiber group (p < 0.05). Gut microbiota analysis revealed that oat fiber increased both the abundance and diversity of gut microbiota in constipated mice. Specifically, oat fiber was found to enhance the relative abundance of Firmicutes while reducing that of Bacteroidetes. At the genus level, it promoted the proliferation of Lachnospiraceae_NK4A136_group and Roseburia. Conclusions: Oat fiber alleviates constipation in mice by modulating gastrointestinal regulatory peptides, gut microbiota, aquaporin and mitigating intestinal barrier damage and immune-inflammatory responses. Full article

Targeted radioligand therapy (RLT) is an emerging field in anticancer therapeutics with great potential across tumor types and stages of disease. While much progress has focused on agents targeting somatostatin receptors and prostate-specific membrane antigen (PSMA), the same advanced radioconjugation methods and molecular targeting have spurred the development of numerous theranostic combinations for other targets. A number of the most promising agents have progressed to clinical trials and are poised to change the landscape of positron emission tomography (PET) imaging. Here, we present recent data on some of the most important emerging molecular targeted agents with their exemplar clinical images, including agents targeting fibroblast activation protein (FAP), hypoxia markers, gastrin-releasing peptide receptors (GRPrs), and integrins. These radiopharmaceuticals share the promising characteristic of being able to image multiple types of cancer. Early clinical trials have already demonstrated superiority to ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for some, suggesting the potential to supplant this longstanding PET radiotracer. Here, we provide a primer for practicing radiologists, particularly nuclear medicine clinicians, to understand novel PET imaging agents and their clinical applications, as well as the availability of companion targeted radiotherapeutics, the status of their regulatory approval, the potential challenges associated with their use, and the future opportunities and perspectives. Full article

Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially improves staging, stratification, and therapy of cancer patients. This study explores a dual-tracer SPECT approach using [¹¹¹In]In-RM2 (targeting the gastrin-releasing peptide receptor, GRPR) and [^99mTc]Tc-PSMA-I&S (targeting the prostate-specific membrane antigen, PSMA) as a proof of concept. To mimic heterogeneous tumor lesions in the same individual, we aimed to establish a dual xenograft mouse model for preclinical evaluation. Methods: CHO-K1 cells underwent lentiviral transduction for human GRPR or human PSMA overexpression. Six-to-eight-week-old female immunodeficient mice (NOD SCID) were subsequently inoculated with transduced CHO-K1 cells in both flanks, enabling a dual xenograft with similar target density and growth of both xenografts. Respective dual-isotope imaging and γ-counting protocols were established. Target expression was analyzed ex vivo by Western blotting. Results: In vitro studies showed similar target-specific binding and internalization of [¹¹¹In]In-RM2 and [^99mTc]Tc-PSMA-I&S in transduced CHO-K1 cells compared to reference lines PC-3 and LNCaP. However, in vivo imaging showed negligible tumor uptake in xenografts of the transduced cell lines. Ex vivo analysis indicated a loss of the respective biomarkers in the xenografts. Conclusions: Although the technical feasibility of a dual-tracer SPECT imaging approach using ¹¹¹In and ^99mTc has been demonstrated, the potential of [^99mTc]Tc-PSMA-I&S and [¹¹¹In]In-RM2 in a dual-tracer cocktail to improve PCa diagnosis could not be verified. The animal model, and in particular the transduced cell lines developed exclusively for this project, proved to be unsuitable for this purpose. The in/ex vivo experiments indicated that results from an in vitro model may not necessarily be successfully transferred to an in vivo setting. To assess the potential of this dual-tracer concept to improve PCa diagnosis, optimized in vivo models are needed. Nevertheless, our strategies address key challenges in dual-tracer applications, aiming to optimize future SPECT imaging approaches. Full article

Aging is associated with structural and functional changes in the gastrointestinal tract; however, its impact on gastric secretion remains unclear. This scoping review examines whether gastric secretion declines with age and explores its clinical implications. Following the PRISMA guidelines, PubMed, Web of Science, Embase, and Google Scholar were systematically searched from inception to December 2024. Fifteen studies (both animal and human) met the inclusion criteria: they were written in English, directly relevant to aging and gastric secretion, and had a clearly stated methodology. Evidence strength was assessed using the GRADE framework, revealing predominantly low to moderate certainty due to small sample sizes and observational study designs. Animal studies have demonstrated reduced acid secretion in older rats, which is attributed to mucosal atrophy and diminished responsiveness to gastrin. Recent human studies suggest that aging does not directly reduce acid output, as reduced acid secretion may result from a higher prevalence of atrophic gastritis, Helicobacter pylori infection, and the widespread use of proton pump inhibitors. Antisecretory therapy may lack benefits in older adult patients with hypochlorhydria/achlorhydria and increase the risk of adverse effects. Pepsin output declines with aging due to reduced chief cell function, although its clinical impact on digestion is unclear. Since intrinsic factor secretion far exceeds the amount necessary for its physiological function, even low amounts seem to be sufficient to prevent cobalamin deficiency. Age-related decline in gastric secretion is mostly attributed to age-associated disorders; however, impairment of secretory function in older people is frequent. Future research should prioritise longitudinal studies, larger cohorts, and histology-stratified analysis. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity. Full article

Neuroendocrine transformation in non-small-cell lung cancer (NSCLC) is an uncommon but clinically significant resistance mechanism to targeted therapy, immunotherapy, and chemotherapy. This phenomenon, primarily observed in adenocarcinoma (ADC) with EGFR mutations under tyrosine kinase inhibitor (TKI) treatment, leads to histological transformation into small-cell lung cancer (SCLC), commonly associated with an aggressive clinical course and poor prognosis. Standard platinum–etoposide chemotherapy provides only transient disease control, highlighting the urgent need for improved therapeutic strategies. Early identification of transformation through biopsy, liquid biopsy, or biomarkers like neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (pro-GRP) may allow for early intervention. As targeted therapies continue to develop, understanding the molecular drivers of neuroendocrine transformation is crucial for optimizing treatment. Further research into novel treatment approaches, including combination therapies with TKIs, chemotherapy, immunotherapy, and epigenetic modulators, is required to improve outcomes for these patients. Full article

Effective molecular imaging and targeted cancer therapy rely on receptor-specific targeted delivery systems that are both metabolically stable and kinetically inert for optimal in vivo performance. Until now, no single metal complexing agent has demonstrated the versatility to coordinate metals across the periodic table while maintaining the kinetic inertness required for clinical theranostic applications. Therefore, enhancing the in vivo kinetic stability of radiolabeled, cell-targeting, biologically active compounds remains a critical goal to minimize unintended accumulation of radioactivity in collateral tissues. This review describes the usage of NOTA [NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid] and derivatives of NOTA, a metal complexing agent that has been found to have the ability to effectively coordinate with a wide range of radiometals, including metal-radiohalogens, to form stable complexes. This enables the development of new cell-targeting small molecule and peptide conjugates with the potential to resist demetallation in vivo, thereby reducing radionuclide uptake in non-target tissues. Herein, we discuss the design and development of NOTA-based, cell-targeting, small molecules having very high affinity and selectivity for the GRPR (Gastrin-Releasing Peptide Receptor), the SSTR2 (Somatostatin Receptor Subtype 2), and the MC1R (Melanocortin-1) receptors that are present on the surfaces of numerous solid primary human tumors and their metastatic counterparts. Full article

The peptidergic systems are involved in neuroblastoma. Peptides (angiotensin II, neuropeptide Y, neurotensin, substance P) act as oncogenic agents in neuroblastoma, whereas others (adrenomedullin, corticotropin-releasing factor, urocortin, orexin) exert anticancer effects against neuroblastoma. This plethora of peptidergic systems show the functional complexity of the mechanisms regulated by peptides in neuroblastoma. Peptide receptor antagonists act as antineuroblastoma agents since these compounds counteracted neuroblastoma cell growth and migration and the angiogenesis promoted by oncogenic peptides. Other therapeutic approaches (signaling pathway inhibitors, focal adhesion kinase inhibitors, peptide receptor knockdown, acetic acid analogs) that also counteract the beneficial effects mediated by the oncogenic peptides in neuroblastoma are discussed, and future research lines to be developed in neuroblastoma (interactions between oncogenic and anticancer peptides, combination therapy using peptide receptor antagonists and chemotherapy/radiotherapy) are also suggested. Although the data regarding the involvement of the peptidergic systems in neuroblastoma are, in many cases, fragmentary or very scarce for a particular peptidergic system, taken together, they are quite promising with respect to potentiating and developing this research line with the aim of developing new therapeutic strategies to treat neuroblastoma in the future. Peptidergic systems are potential and promising targets for the diagnosis and treatment of neuroblastoma. Full article

Background/Objectives: Periostracum Cicadae (PC) is commonly used to treat chronic atrophic gastritis (CAG), but its underlying mechanisms are unclear. We investigated the therapeutic effects, active ingredients and molecular mechanisms of PC on CAG. Methods: We analyzed the components in the serum extract of PC by UHPLC-Q-Orbitrap-MS/MS. Then, we used rat and cell models to assess the impact of PC on CAG and employed network pharmacology and bioinformatics to predict key targets and active ingredients. Finally, we confirmed hub targets through experiments and molecular docking. Results: A total of 22 components were identified in the PC extract-containing serum using UHPLC-Q-Orbitrap MS/MS. Network pharmacology combined with molecular docking revealed that the protective effect was primarily mediated by three compounds: (Z)-akuammidine, chicoric acid, and columbianadin. And we revealed that c-Fos/c-Jun signaling pathways were crucial in therapy. PC extract-containing serum inhibited the vitality, migration, invasion, and multiplication of MC cells (model cells for CAG), induced apoptosis, and caused G0/G1 phase cell cycle arrest. The expression level of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β) and gastrin 17 (G17) in the serum of CAG rats increased, while the expression level of pepsinogen I (PG I) and pepsinogen II (PG II) decreased. After 12 weeks of PC administration, these conditions were significantly improved. PC not only reduced the levels of antigen KI-67 (Ki67) and tumor protein p53 (P53) but also enhanced SRY-box Transcription Factor (SOX2). Simultaneously, PC down-regulated the expression of N-cadherin and Vimentin while up-regulating that of E-cadherin. Conclusions: PC inhibited epithelial–mesenchymal transition (EMT) via the c-Fos/c-Jun signaling pathway, thereby providing therapeutic benefits for CAG. Our study elucidates the mechanisms and material basis of PC in treating CAG, providing experimental evidence to support its clinical application. Full article

Background/Objectives: Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one ⁶⁸Ga-labeled GRPR antagonist, [⁶⁸Ga]Ga-TacsBOMB5 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,NMe-Gly¹¹,Leu¹³ψThz¹⁴]Bombesin(6–14)), and two agonists, [⁶⁸Ga]Ga-LW01110 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6–14)) and [⁶⁸Ga]Ga-LW01142 (⁶⁸Ga-DOTA-Pip-[D-Phe⁶,His⁷,Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(6–14)) showing minimal pancreas uptake. Thus, in this study, we prepared their ¹⁷⁷Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [¹⁷⁷Lu]Lu-AMBA. Methods: GRPR binding affinities were determined by in vitro competition binding assay using PC-3 prostate cancer cells. Longitudinal SPECT/CT imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Dosimetry data were calculated from the biodistribution results. Results: The K_i(GRPR) values of Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were 12.6 ± 1.02, 3.07 ± 0.15, 2.37 ± 0.28, and 0.33 ± 0.16 nM, respectively. SPECT/CT images and biodistribution results demonstrated good tumor accumulation of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz¹⁴]Bombesin(6–14)-derived ligands was significantly lower than that of [¹⁷⁷Lu]Lu-AMBA at all time points. The calculated absorbed doses of [¹⁷⁷Lu]Lu-TacsBOMB5, [¹⁷⁷Lu]Lu-LW01110, and [¹⁷⁷Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [¹⁷⁷Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [¹⁷⁷Lu]Lu-RM2 (429 mGy/MBq). Conclusions: Our data suggest that [¹⁷⁷Lu]Lu-TacsBOMB5 and [¹⁷⁷Lu]Lu-LW01142 reduce radiation exposure to the pancreas. However, further optimizations are needed for both radioligands to prolong their tumor retention and enhance treatment efficacy. Full article

Royal jelly (RJ) has long been considered a crucial dietary component in dictating caste differentiation in honeybees. As a nutritional additive, royal jelly imparts a broad range of benefits to mammals and humans; however, its precise impact on the social hierarchy of these advanced animals is not yet fully understood. This study aims to determine whether the benefits of royal jelly can be transferred to rats to alter their social ranks and uncover the underlying mechanisms. A submissive model was established by inducing dysbiosis in rats, via the persistent exposure of vancomycin. Royal jelly at a dose of 2.5 g/kg was daily administered to the subject rats during postnatal weeks (PNW) 6 and 7. At the end of the intervention, animals were subjected to agonistic, water and tube competition tests, in order to assess their dominance status. As revealed by the results, the RJ treatment significantly improved the social rank of the dysbiotic rats, demonstrating that RJ can elicit positive effect on the social behaviors (caused by dysbiosis) of rats. All behavioral paradigms yielded consistent results, with no notable differences in body weight or anxiety levels. Regarding gut microbiome, vancomycin exposure caused the dysbiosis of the subject rats, which was partially reversed by treatment with royal jelly. Specifically, the intestinal presence of Proteobacteria was profoundly attenuated by the RJ supplementation, resulting in a comparable level with the intact/dominant rats. At the genus level, both Escherichia and Clostridium displayed similar dynamics in relation to Proteobacteria, implying their involvement with the RJ-mediated dominance switching. Transcriptomic analysis in the medial prefrontal context showed that the expression of a broad range of genes was influenced by RJ intake, embodying various pathways related to neuronal transmission such as neuroactive ligan–receptor interaction, the synaptic vesicle cycle, etc. By virtue of correlation analysis, Escherichia, Akkermansia and Clostridium were strongly associated with a set of gene modules around gastrin releasing peptide (Grp) and signaling pathways around Rps6ka3, establishing an intrinsic gut–brain communication. Furthermore, the infection trials of Escherichia significantly degraded the social ranks of the RJ-remedied rats in tube tests, while a series of cerebral genes like Grpr and Grpel1, as well as prefrontal spine density, were concordantly altered, underscoring the critical role of the gut–brain link in deciding the outcomes of the dyadic contests. In summary, this is an intriguing example of how royal jelly can influence the social ranks of mammals, emphasizing the importance of microbe–host interaction in mediating this species-spanning function of royal jelly in shaping social hierarchy. Full article

Bombesin receptor subtype-3 (BRS-3) is a type 1 G-protein-coupled receptor (GPCR). BRS-3 is an orphan GPCR that is structurally related to neuromedin B and gastrin-releasing peptide receptors. When activated, BRS-3 causes phosphatidylinositol turnover in lung cancer cells. BRS-3 stimulates tyrosine the phosphorylation of the epidermal growth-factor receptor (ErbB1); however, it is unknown whether it transactivates ErbB2/HER2. Adding the nonpeptide BRS-3 allosteric agonist MK-5046 or the peptide agonist BA1 to the lung cancer cell line NCI-H727 or to BRS-3-transfected NCI-H1299 lung cancer cells increased the tyrosine phosphorylation of HER2/ERK2. This increase was antagonized by the BRS-3 peptide antagonist Bantag-1 and the small-molecule BRS-3 antagonist ML-18. The increase in HER2/ERK phosphorylation caused by MK-5046 was inhibited by the ROS inhibitors N-acetylcysteine and Tiron (superoxide scavengers). Adding MK-5046 to lung cancer cells increased reactive oxygen species, which was inhibited by NAC or Tiron. MK-5046 and BA1 increased non-small lung cancer cell (NSCLC) colony formation, whereas Bantag-1/ML-18 inhibited proliferation. These results indicate that in lung cancer cells, the activation of BRS-3 regulates HER2 transactivation in an ROS-dependent manner, which can mediate tumor growth. These results raise the possibility that the use of HER2-inhibiting compounds alone or in combination with other agents could represent a novel approach to the treatment of these tumors. Full article