Drug Development Research最新文献

{"title":"PARP7i Clinical Candidate RBN-2397 Exerts Antiviral Activity by Modulating Interferon-β Associated Innate Immune Response in Macrophages","authors":"Xiaoli Du,&nbsp;Jiawei Zhou,&nbsp;Yi Zhou,&nbsp;Yulong Chen,&nbsp;Yanhua Kang,&nbsp;Dongjiu Zhao,&nbsp;Xiang-Yang Ye,&nbsp;Liwei Wang,&nbsp;Tian Xie,&nbsp;Hang Zhang","doi":"10.1002/ddr.70013","DOIUrl":"10.1002/ddr.70013","url":null,"abstract":"<div>\u0000 \u0000 <p>Polyadenosine diphosphate-ribose polymerase 7 (PARP7) acts as a suppressor of the type I interferon (IFN) signaling pathway via suppressing TANK-binding protein 1 (TBK1). Research study indicates that inhibition of PARP7 could potentially regulate tumor immunity. However, the effect of PARP7 inhibition on innate antiviral immunity in macrophages as well as the underlying mechanism have not been demonstrated else well. We report herein that PARP7 inhibitor clinical candidate RBN-2397 could augment type I interferon (IFN-I) production in macrophages by elevating retinoic acid-inducible gene I (RIG-I) and stimulator of interferon genes (STING) signaling pathways. Treatment with RBN-2397 leads to increased pattern recognition ligands-induced interferon-β production in primary bone marrow-derived macrophages (BMDM) and RAW264.7 cells. Additionally, RBN-2397 suppresses viral replication efficiency in macrophages infected by vesicular stomatitis virus (VSV) and amplifies the expression of interferon-stimulated chemokine genes (ISGs). Mechanistically, RBN-2397 promotes TBK1 phosphorylation, consequently leading to the amplified activation of RIG-I and STING signaling pathways. Furthermore, RBN-2397 enhances the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 induced by IFN-α/β and the expression of chemokine genes in macrophages in response to IFN stimulation. In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MLLT3 knockdown suppresses proliferation and cell mobility in human lung adenocarcinoma","authors":"Wenbo Shi,&nbsp;Tongyangzi Zhang,&nbsp;Li Zhang,&nbsp;Wanzhen Li,&nbsp;Zhiwei Chen,&nbsp;Xianghuai Xu","doi":"10.1002/ddr.70010","DOIUrl":"10.1002/ddr.70010","url":null,"abstract":"<p>Lung cancer is emerging as one of the most frequently encountered malignancies around the world that carries high morbidity and mortality. Lung adenocarcinoma (LUAD) has become the most common subtype of lung cancer. MLLT3 or named AF9 was first characterized in acute myeloid leukemia and can downregulate the expression of several critical genes. The aim of this study was to explore the function of MLLT3 in the progression of LUAD and related molecular mechanisms. Immunohistochemistry was employed to assess MLLT3 expression in LUAD tissues, while quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were utilized to detect MLLT3 expression levels in lung adenocarcinoma cell lines. These results revealed a significant overexpression of MLLT3 in LUAD cell lines and tissues. We further uncovered an association between MLLT3 expression profiles in LUAD tissues and metastasis, as well as TNM stage. Survival analysis showed that elevated MLLT3 correlated with a poorer survival rate. We also found that MLLT3 knockdown repressed LUAD cells invasion, migration, and proliferation in vitro, while inducing cell cycle arrest and apoptosis of LUAD cells. Moreover, knocking down MLLT3 inhibited tumor growth in vivo. Specific markers of apoptosis, cell cycle, epithelial-mesenchymal transition (EMT), and MLLT3-induced signaling were examined by Western blot. We demonstrated that MLLT3 knockdown inhibited the activity of the EGFR-MAPK/ERK signaling pathway, and MLLT3 might be a novel diagnostic biomarker and therapeutic target in lung adenocarcinomas.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted therapies for Glioblastoma multiforme (GBM): State-of-the-art and future prospects","authors":"Smera Satish,&nbsp;Maithili Athavale,&nbsp;Prashant S. Kharkar","doi":"10.1002/ddr.22261","DOIUrl":"10.1002/ddr.22261","url":null,"abstract":"<p>Glioblastoma multiforme (GBM) remains one of the most aggressive and lethal forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. The present review explores the latest advancements in targeted therapies for GBM, emphasizing the critical role of the blood-brain barrier (BBB), blood-brain-tumor barrier, tumor microenvironment, and genetic mutations in influencing treatment outcomes. The impact of the key hallmarks of GBM, for example, chemoresistance, hypoxia, and the presence of glioma stem cells on the disease progression and multidrug resistance are discussed in detail. The major focus is on the innovative strategies aimed at overcoming these challenges, such as the use of monoclonal antibodies, small-molecule inhibitors, and novel drug delivery systems designed to enhance drug penetration across the BBB. Additionally, the potential of immunotherapy, specifically immune checkpoint inhibitors and vaccine-based approaches, to improve patient prognosis was explored. Recent clinical trials and preclinical studies are reviewed to provide a comprehensive overview of the current landscape and future prospects in GBM treatment. The integration of advanced computational models and personalized medicine approaches is also considered, aiming to tailor therapies to individual patient profiles for better efficacy. Overall, while significant progress has been made in understanding and targeting the complex biology of GBM, continued research and clinical innovation are imperative to develop more effective and sustainable therapeutic options for patients battling this formidable disease.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Agmatine: An Emerging Approach for Neuroprotection in Recurrent Ischemic Stroke Events in a Murine Model","authors":"M. L. Miranda-Mosqueda,&nbsp;S. Y. Ruiz-Oropeza,&nbsp;J. A. González-Barrios,&nbsp;R. Jaimez,&nbsp;Fernando Peña-Ortega,&nbsp;C. Gómez-Acevedo","doi":"10.1002/ddr.70012","DOIUrl":"10.1002/ddr.70012","url":null,"abstract":"<p>This study investigates the effect of agmatine on reducing mortality, neurobehavioral alterations, infarct size, and expression of pro-inflammatory cytokines in mice subjected to bilateral carotid thrombosis. Under pentobarbital anesthesia, the left common carotid artery was exposed to 6% FeCl₃. Thirty-two days later, the same procedure was performed on the right common carotid artery. Subsequently, Agmatine (100 mg/kg) was administered 15 min after the second procedure, and in another experimental group, the dose of Agmatine was repeated at 72 h. Administration of agmatine extended survival in ischemic animals up to 72 h for the single-dose group and up to 96 h for the repeated-dose group, without significant increases in neurological deficits or infarct area size. This neurobehavioral effect was also observed in sham animals treated with agmatine. In ischemic animals, agmatine administration improved digging behavior and reduced recovery times, consistently shorter in those animals treated with repeated doses. RT-PCR analyses revealed a positive regulation of the cytokine IL-1β in agmatine-treated animals, which has been associated with recovery stages. The results suggest that the observed effect may be attributed to the multiple interactions of agmatine with ischemic cascade events, highlighting its anti-inflammatory role.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency","authors":"Faizah A. Binjubair,&nbsp;Basma S. Almansour,&nbsp;Noha I. Ziedan,&nbsp;Alaa A.-M. Abdel-Aziz,&nbsp;Sara T. Al-Rashood,&nbsp;Mohamed K. Elgohary,&nbsp;Mahmoud S. Elkotamy,&nbsp;Hatem A. Abdel-Aziz","doi":"10.1002/ddr.70009","DOIUrl":"10.1002/ddr.70009","url":null,"abstract":"<p>Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4-(3,4-Dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine (<b>3</b>) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5-dose experiment by the NCI/USA. The GI₅₀ values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI₅₀ of 2.70 μM for (MG-MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound <b>3</b>, we optimized its structure using DFT with the B3LYP/6-31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in-silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co-crystallized one. Our findings revealed compound <b>3</b> exhibited better binding for half of the tested kinases, suggesting its potential as a multi-kinase inhibitor. To further validate our computational results, we tested compound <b>3</b> for its inhibitory effects on CDK2 and PIM1. Compound <b>3</b> exhibited an IC₅₀ of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC₅₀ of 0.06 µM. However, compound <b>3</b> demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound <b>3</b> is a promising anticancer agent with the potential for further development into a highly active compound.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA sequencing comparing centenarian and middle-aged women lymphoblastoid cell lines identifies age-related dysregulated expression of genes encoding selenoproteins, heat shock proteins, CD99, and BID","authors":"Irena Voinsky,&nbsp;Ofir Goldenberg-Bogner,&nbsp;Ifat Israel-Elgali,&nbsp;Hadas Volkov,&nbsp;Monika Puzianowska-Kuźnicka,&nbsp;Noam Shomron,&nbsp;David Gurwitz","doi":"10.1002/ddr.70011","DOIUrl":"10.1002/ddr.70011","url":null,"abstract":"<p>Women typically live longer than men, and constitute the majority of centenarians. We applied RNA-sequencing (RNA-seq) of blood-derived lymphoblastoid cell lines (LCLs) from women aged 60-80 years and centenarians (100-105 years), validated the RNA-seq findings by real-time PCR, and additionally measured the differentially expressed genes in LCLs from young women aged 20-35 years. Top RNA-seq genes with differential expression between the age groups included three selenoproteins (<i>GPX1, SELENOW, SELENOH</i>) and three heat shock proteins (<i>HSPA6, HSPA1A, HSPA1B</i>), with the highest expression in LCLs from young women, indicating that young women are better protected from oxidative stress. The expression of two additional genes, <i>BID</i> encoding BH3-interacting domain death agonist and <i>CD99</i> encoding CD99 antigen, showed unique age dependence, with similar expression levels in young and centenarian women while exhibiting higher and lower expression levels, respectively, in LCLs from women aged 60-80 years compared with the two other age groups. This age-related differential expression of <i>BID</i> and <i>CD99</i> suggests elevated inflammation susceptibility in middle-aged women compared with either young or centenarian women. Our findings, once validated with human peripheral blood mononuclear cells and further cell types, may lead to novel healthy aging diagnostics and therapeutics.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of BIX01294 in the intracranial inhibition of H3K9 methylation lessens neuronal loss in vascular dementia model","authors":"Fardin Sehati,&nbsp;Saereh Hosseindoost,&nbsp;Mina Ranjbaran,&nbsp;Fatemeh Nabavizadeh,&nbsp;Seyed-Morteza Karimian,&nbsp;Soheila Adeli,&nbsp;Elham Zahedi,&nbsp;Leila Chodari,&nbsp;Ghorbangol Ashabi","doi":"10.1002/ddr.70001","DOIUrl":"10.1002/ddr.70001","url":null,"abstract":"<p>Dementia develops as a result of multiple factors, including cerebrovascular disease which is called vascular dementia (VD). Histone-3 lysine-9 dimethylation (H3K9me2) broadly increases during VD and inhibits neuroprotective gene expressions. So, we aimed to determine how H3K9me2 inhibitor (BIX01294) affects neuronal damage in VD. An in vivo model of VD was used followed by BIX01294 treatment. Behavioral tests, hematoxylin, and eosin (H&amp;E), Congo red, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were carried out. Hippocampal phosphorylated cyclic-AMP responsive element binding protein (p-CREB), c-fos, brain-derived neurotrophic factor (BDNF), and H3K9me2, were detected by western blot analysis technique. Neurological deficit and anxiety-related behavior significantly reduced in the treatment group compared to the VD group (<i>p</i> &lt; 0.05). BIX01294 improved spatial and passive avoidance memory (<i>p</i> &lt; 0.01 and <i>p</i> &lt; 0.05, respectively) compared to the VD group. Treatment with BIX01294 restored the level of p-CREB/CREB ratio (<i>p</i> &lt; 0.05), cfos (<i>p</i> &lt; 0.01), BDNF (<i>p</i> &lt; 0.01), and suppressed H3K9me2 (<i>p</i> &lt; 0.001) when compared to the VD group. BIX01294 microinjection reduced the apoptosis level in TUNEL staining (<i>p</i> &lt; 0.05), and raised neural cell count in H&amp;E staining (<i>p</i> &lt; 0.01); amyloid beta accumulation significantly decreased in the treatment group (<i>p</i> &lt; 0.05) compared to the VD group. In conclusion, long-term treatment with a low dose of BIX01294 can prevent the progression of neuronal loss in VD model by raising the expression of neurotrophic factors, and reducing the apoptosis level.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and evaluation of novel Indole-Based small molecules as sirtuin inhibitors with anticancer activities","authors":"Busra Binarci,&nbsp;Ensar Korkut Kilic,&nbsp;Tunca Dogan,&nbsp;Rengul Cetin Atalay,&nbsp;Deniz Cansen Kahraman,&nbsp;Sultan Nacak Baytas","doi":"10.1002/ddr.70008","DOIUrl":"https://doi.org/10.1002/ddr.70008","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, driven mainly by chronic hepatitis infections and metabolic disorders, which highlights the urgent need for novel therapeutic strategies. Sirtuins, particularly SIRT1 are crucial in HCC pathogenesis, making it a promising drug target. Indole-based molecules show potential as therapeutic agents by interacting with key proteins like sirtuins involved in cancer progression. In this study, we designed and synthesized novel indole-based small molecules and investigated their potential sirtuin inhibitory action and anticancer activity on HCC cell lines. Four of the twenty-eight tested small molecules on different cancer types were selected (<b>4 g</b>, <b>4 h</b>, <b>4o</b>, and <b>7j</b>) based on their structure–activity relationship and studied on a panel of HCC cell lines. Compounds had active drug-target interactions with SIRT1 or SIRT2 based on DEEPScreen DTI predictions and docking studies which confirmed that <b>4o</b>, <b>4 g</b>, and <b>7j</b> were most potent in their interaction with SIRT1. Compound <b>4 g</b> caused the highest sirtuin activity inhibition in vitro and induced G1 arrest and apoptosis in HCC cell lines.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway","authors":"Safaa E. Seif,&nbsp;Wagnat W. Wardakhan,&nbsp;Rasha A. Hassan,&nbsp;Amr M. Abdou,&nbsp;Zeinab Mahmoud","doi":"10.1002/ddr.70007","DOIUrl":"https://doi.org/10.1002/ddr.70007","url":null,"abstract":"<p>Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-<i>d</i>]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives <b>5b</b>, <b>5f</b>, and <b>9c</b> showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound <b>9c</b> showed the highest activity with IC₅₀ = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC₅₀ = 2.556 ± 0.09 µM and SI = 6.19. Compound <b>9c</b> was also the most potent against B-RAF^WT and mutated B-RAF^V600E with IC₅₀ = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC₅₀ = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that <b>9c</b> increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound <b>9c</b> displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound <b>9c</b> increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of <b>9c</b> with the B-RAF active site.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of short-stature homeobox protein 2 suppresses gastric cancer cell growth and stemness in vitro and in vivo via inactivating wnt/β-catenin signaling","authors":"Xiangyu Chen,&nbsp;Shuai Li,&nbsp;Binghua Sun","doi":"10.1002/ddr.70006","DOIUrl":"https://doi.org/10.1002/ddr.70006","url":null,"abstract":"<p>Gastric cancer (GC) a prevalent form of cancer globally. Previous research suggests that SHOX2 may have a role in promoting cancer progression. However, the role of SHOX2 in GC is not well understood. Based on data from TCGA_GC data set, SHXO2 levels were examined in normal and GC tissues. Patients in the TCGA_GC cohort were divided into high- and low-SHOX2 level groups for analysis of overall survival (OS), functional enrichment, and immune infiltration. Furthermore, experiments were conducted to investigate the impact of SHOX2 on GC cell function through gain- and loss-of-function experiments. Utilizing data from public databases, SHOX2 mRNA levels were found to be elevated in GC tissues compared to normal control, this finding was confirmed by RT-qPCR, western blot analysis, and immune-histochemical analyses. Elevated SHOX2 levels could serve as an independent indicator of poor prognosis in GC patients. Furthermore, SHOX2 levels had a negative correlation with CD8 T cells and CD4 memory activated T cells, and a positive correlation with of M0 macrophages in GC patients. Functional analyses revealed that SHOX2 deficiency notably suppressed GC cell proliferation, migration, and invasion. Additionally, SHOX2 deficiency was shown to suppress stemness in GC cells in vitro and in vivo via inactivating wnt/β-catenin signaling. Collectively, SHOX2 may serve as a prognostic marker for GC patients, and downregulation of SHOX2 could effectively impede GC cell growth and stemness by inactivating the wnt/β-catenin signaling pathway. These findings underscore the potential of SHOX2 as a promising therapeutic target for GC.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}