Biomedicine & Pharmacotherapy最新文献

{"title":"Pharmacokinetic modeling of prenatal vitamin D exposure and the impact on offspring asthma and pulmonary function","authors":"Iskander L.C. Shadid ,&nbsp;Nicklas Brustad ,&nbsp;Bo L. Chawes ,&nbsp;Dirk Jan A.R. Moes ,&nbsp;Scott T. Weiss ,&nbsp;Henk-Jan Guchelaar ,&nbsp;Hooman Mirzakhani","doi":"10.1016/j.biopha.2025.117859","DOIUrl":"10.1016/j.biopha.2025.117859","url":null,"abstract":"<div><div>Gestational 25-hydroxyvitamin D (25[OH]D) is important in fetal lung development and may influence offspring respiratory outcomes, making accurate exposure assessment essential to understand clinical associations. Therefore, we used the combined data from two large RCTs investigating prenatal vitamin D supplementation, which included early and late prenatal 25(OH)D measurements, to refine a population pharmacokinetic model of vitamin D-25(OH)D and estimate individual area under the curve (AUC) Z-scores. The primary outcome was physician-diagnosed offspring asthma/wheezing at ages 3 and 6 years, and lung function, as a secondary outcome, was evaluated by spirometry at the ages 6 and 8 years. In total, 1319 mother-child pairs were included. We found that clearance of 25(OH)D increased with gestational age and bodyweight, and decreased with higher baseline 25(OH)D levels. Prenatal 25(OH)D AUC Z-scores were negatively associated with asthma/wheezing at age 3 years (aOR = 0.75, 95 % CI = 0.64–0.88, <em>p</em> &lt; 0.001) and 6 years (aOR = 0.83, 95 % CI = 0.72–0.95, <em>p</em> = 0.008). Longitudinal analysis of lung function from age 6–8 years showed that AUC Z-scores were positively associated with percent-predicted FEV₁ (β = 1.2₁%, 95 % CI = 0.30–2.11; <em>p</em> = 0.009), FVC (β = 0.79 %, 95 % CI = 0.13–1.46; <em>p</em> = 0.021), FEV₁/FVC ratio (β = 0.56 %, 95 % CI = 0.11–1.01; <em>p</em> = 0.015) and FEF_25–75 % (β = 2.18 %, 95 % CI = 0.46–3.91; <em>p</em> = 0.009). These results together indicate an exposure-outcome relationship where higher gestational 25(OH)D exposure, estimated by AUC, is associated with reduced childhood asthma/recurrent wheeze and improved lung function.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117859"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer drug resistance as learning of signaling networks","authors":"Dávid Keresztes ,&nbsp;Márk Kerestély ,&nbsp;Levente Szarka ,&nbsp;Borbála M. Kovács ,&nbsp;Klára Schulc ,&nbsp;Dániel V. Veres ,&nbsp;Peter Csermely","doi":"10.1016/j.biopha.2025.117880","DOIUrl":"10.1016/j.biopha.2025.117880","url":null,"abstract":"<div><div>Drug resistance is a major cause of tumor mortality. Signaling networks became useful tools for driving pharmacological interventions against cancer drug resistance. Signaling datasets now cover the entire human cell. Recently, network adaptation became understood as a learning process. We review rapidly increasing evidence showing that the development of cancer drug resistance can be described as learning of signaling networks. During drug adaptation, the network forgets drug-affected pathways by desensitization and relearns by strengthening alternative pathways. Thus, resistant cancer cells develop a drug resistance memory. We show that all key players of cellular learning (i.e., IDPs, protein translocation, microRNAs/lncRNAs, scaffolding proteins and epigenetic/chromatin memory) have important roles in the development of cancer drug resistance. Moreover, all of them are central components of the epithelial-mesenchymal transition leading to metastases and resistance. Phenotypic plasticity was recently listed as a hallmark of cancer. We review how network plasticity induces rare, pre-existent drug-resistant cells in the absence of drug treatment. Key network methods assessing the development of drug resistance and network pharmacological interventions against drug resistance are summarized. Finally, we highlight the class of cellular memory drugs affecting cellular learning and forgetting, and we summarize current challenges to prevent or break drug resistance using network models.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117880"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small-molecule activators of NRF1 transcriptional activity prevent protein aggregation","authors":"Jindrich Sedlacek ,&nbsp;Zuzana Smahelova ,&nbsp;Michael Adamek ,&nbsp;Dominika Subova ,&nbsp;Lucie Svobodova ,&nbsp;Alena Kadlecova ,&nbsp;Pavel Majer ,&nbsp;Ales Machara ,&nbsp;Klara Grantz Saskova","doi":"10.1016/j.biopha.2025.117864","DOIUrl":"10.1016/j.biopha.2025.117864","url":null,"abstract":"<div><div>Intracellular protein aggregation causes proteotoxic stress, underlying highly debilitating neurodegenerative disorders in parallel with decreased proteasome activity. Nevertheless, under such stress conditions, the expression of proteasome subunits is upregulated by Nuclear Factor Erythroid 2-related factor 1 (NRF1), a transcription factor that is encoded by <em>NFE2L1</em>. Activating the NRF1 pathway could accordingly delay the onset of neurodegenerative and other disorders with impaired cell proteostasis. Here, we present a series of small-molecule compounds based on bis(phenylmethylen)cycloalkanones and their heterocyclic analogues, identified via targeted library screening, that can induce NRF1-dependent downstream events, such as proteasome synthesis, heat shock response, and autophagy, in both model cell lines and <em>Caenorhabditis elegans</em> strains. These compounds increase proteasome activity and decrease the size and number of protein aggregates without causing any cellular stress or inhibiting the ubiquitin-proteasome system (UPS). Therefore, our compounds represent a new promising therapeutic approach for various protein conformational diseases, including the most debilitating neurodegenerative diseases.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117864"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Circular RNA circHIAT1 inhibits cell growth in hepatocellular carcinoma by regulating miR-3171/PTEN axis” [Biomed. Pharmacother. 116 (2019) 108932]","authors":"Zhengmiao Wang ,&nbsp;Yixuan Zhao ,&nbsp;Ye Wang ,&nbsp;Chunxiang Jin","doi":"10.1016/j.biopha.2025.117807","DOIUrl":"10.1016/j.biopha.2025.117807","url":null,"abstract":"","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117807"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective role of mirabegron: Targeting beta-3 adrenergic receptors to alleviate ulcerative colitis-associated cognitive impairment","authors":"Salma Nasser ,&nbsp;Hanan S. El-Abhar ,&nbsp;Nabila El-Maraghy ,&nbsp;Dalaal M. Abdallah ,&nbsp;Walaa Wadie ,&nbsp;Suzan Mansour","doi":"10.1016/j.biopha.2025.117816","DOIUrl":"10.1016/j.biopha.2025.117816","url":null,"abstract":"<div><div>While cognitive impairment has been documented in ulcerative colitic patients, the possible influence of central β3-adrenergic receptor (β3-AR) signaling on this extraintestinal manifestation remains unclear. Previously, we identified an imperative role for mirabegron (MA) as an agonist of β3-AR, in decreasing the BACE-1/beta-amyloid (Aβ) cue in the colons of UC rats. Consequently, we investigated its therapeutic potential for alleviating cognitive impairment associated with UC. To fulfil our aim, rats administered iodoacetamide were treated with the β3-AR agonist (MA) alone, with the antagonist (SR59230A) for 8 days, or kept untreated. The animals' behavior (MWM and NOR tests) and hippocampal structure were assessed. Mechanistically, necroptosis, ER stress (ERS), Aβ-amyloidosis, inflammation/oxidative burden, and gut/BBB dysfunction were analyzed. Post-administration of MA improved weight gain, colon/hippocampal structures, and memory. Additionally, it inhibited serum levels of lipopolysaccharide and Annexin-1, indicating recovered gut and BBB integrity. MA turned off the pathogenic BACE-1/Aβ axis in the hippocampus, necroptosis trajectory (TNFR-1/RIPK1/RIPK3/MLKL), and the IRE-1α/JNK signal. Moreover, MA enhanced the transcription factor PPAR-γ, decreased NF-κΒ/TNF-α inflammatory hub, and modulated the redox imbalance by decreasing malondialdehyde and increasing catalase. Notably, MA’s behavioral, structural, and molecular beneficial actions were hindered by the pre-administration of SR59230A. From a novel standpoint, we recognized the β3-AR as a therapeutic target for UC-associated cognitive impairment in the hippocampus. In this context, the aptitude of MA to inhibit UC-induced hippocampal amyloidogenesis, alongside its anti-necroptotic, anti-ERS, anti-inflammatory, and antioxidant effects, contribute to these central enhancements, while also regulating permeability in both gut and BBB barriers.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117816"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CK-666 exerts anticancer effects by regulating autophagy, tunneling nanotubes and extracellular vesicles formation","authors":"Lei Li ,&nbsp;Suli Cai ,&nbsp;Jie Chen ,&nbsp;Zheyu Yin ,&nbsp;Jianli Liu ,&nbsp;Susu Shi ,&nbsp;Wei Wang","doi":"10.1016/j.biopha.2025.117825","DOIUrl":"10.1016/j.biopha.2025.117825","url":null,"abstract":"<div><div>CK-666, an inhibitor of the actin-related protein complex 2/3 (Arp2/3), can suppress lamellipodia formation and cell migration. However, research on its application in tumor therapy is still limited. Using RNA-seq, we clustered and analyzed the functions of differentially expressed mRNAs in CK-666-treated tumor cells. Interestingly, the differentially expressed genes related to CK-666 were closely associated with exosomes and autophagy. Through Western blot, we confirmed that CK-666 promoted the high expression of exosome and autophagy markers in tumor cells. Transmission electron microscopy results indicated the appearance of extracellular vesicles larger than exosomes. Scanning electron microscopy findings revealed that CK-666 inhibited the formation of intercellular tunneling nanotubes (TNTs). Fluorescent staining further revealed that CK-666 induced the formation and secretion of CD63-positive vesicles within the tunnels of retraction fibers (RFs). In vitro experiments verified that CK-666 preferentially inhibited fibroblasts in 3D tumorspheres. In the tumor 3D-Histoculture Drug Response Assay (3D-HDRA), it was found that CK-666 could suppress the activity of isolated tumor tissues. Moreover, our study discovered that the combination of CK-666 and docetaxel (DTX) significantly enhanced DTX sensitivity. In summary, our results suggest that CK-666 may play an oncogenic role by regulating autophagy, TNTs, and extracellular vesicles formation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117825"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual effect of targeting LSD1 on the invasiveness and the mechanical response of acute lymphoblastic leukemia cells","authors":"Raquel González-Novo ,&nbsp;Marina Armesto ,&nbsp;África González-Murillo ,&nbsp;Marcel Dreger ,&nbsp;Adam F.L. Hurlstone ,&nbsp;Ana Benito ,&nbsp;Rafael Samaniego ,&nbsp;Manuel Ramírez ,&nbsp;Javier Redondo-Muñoz","doi":"10.1016/j.biopha.2025.117830","DOIUrl":"10.1016/j.biopha.2025.117830","url":null,"abstract":"<div><div>Epigenetic alterations are hallmarks of cancer, with histone modifiers playing critical roles in gene transcription, DNA homeostasis, and other nuclear functions. Lysine-specific demethylase 1 (LSD1), a key regulator of H3K4 methylation, has emerged as a promising pharmacological target in cancer treatment, including leukemia. Acute lymphoblastic leukemia (ALL), the most common pediatric cancer, remains a significant therapeutic challenge due to limited understanding of how epigenetic therapy impacts leukemia dissemination. In this study, we demonstrate that targeting LSD1 enhances the invasive capacity of ALL cells, inducing an elongated, invasive phenotype and increasing nuclear deformability. Using a 3D matrix model, LSD1 inhibition promoted ALL cell invasion without significantly affecting the cell cycle progression or apoptosis under the tested conditions. Interestingly, LSD1 targeting reduced ALL cell spreading and tissue colonization <em>in vivo</em>, suggesting differential effects depending on the cellular context. Our findings indicate that LSD1 inhibition impairs chemotactic responses and transendothelial migration, key processes for extravasation and in vivo invasiveness. These results reveal a dual role for LSD1 in leukemia cell migration: promoting invasiveness in 3D environments while reducing extravasation and chemotaxis <em>in vivo</em>. This dual effect underscores the importance of cellular context in determining therapeutic outcomes and the development of strategies targeting specific stages of leukemia dissemination.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117830"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRP3 promoter methylation as a predictive biomarker for glucocorticoid response in patients with inflammatory bowel disease","authors":"Giulia Zudeh ,&nbsp;Davide Selvestrel ,&nbsp;Matteo Bramuzzo ,&nbsp;Erika Cecchin ,&nbsp;Monica D’Andrea ,&nbsp;Biljana Stankovic ,&nbsp;Nikola Kotur ,&nbsp;Branka Zukic ,&nbsp;Sanja Dragasevic ,&nbsp;Giuliana Decorti ,&nbsp;Gabriele Stocco ,&nbsp;Marianna Lucafò","doi":"10.1016/j.biopha.2025.117824","DOIUrl":"10.1016/j.biopha.2025.117824","url":null,"abstract":"<div><div>Glucocorticoids are used for inflammatory bowel disease (IBD) therapy; however nearly 50 % of IBD patients exhibit resistance or dependence. This study evaluates the relationship between methylation level at two CpG sites (cg21991396 and cg00448525) within <em>NLRP3</em> promoter and glucocorticoid response of 94 IBD pediatrics (39 with Crohn's disease (40.4 %)) and 47 IBD adults (26 with Crohn's disease (55.3 %)). Disease activity scores were collected before the treatment, after the first full-dose reduction and after 3 months of therapy. Patients with active disease despite receiving a standard dose of prednisone were considered resistant, while those who initially responded but relapsed upon dose reduction were classified as dependent. The DNA methylation was investigated through sodium bisulfite conversion followed by pyrosequencing. In IBD adults, methylation levels at both <em>NLRP3</em> CpG sites increased with patients’ age (p = 0.0038 and p = 0.0018, respectively). In IBD pediatrics, the methylation level at both CpG sites negatively correlated with the disease activity score before treatment (p = 0.031 and p = 0.072, respectively) and after 1 month of therapy (p = 0.037 and p = 0.067, respectively). Furthermore, poor glucocorticoid response after one month of therapy in pediatric patients was associated with lower methylation levels at both CpG sites (p = 0.045 and p = 0.038, respectively). Crohn’s disease patients had higher percentage of good responders compared to ulcerative colitis patients (p = 0.06). These findings indicate that <em>NLRP3</em> methylation might change through patients’ lifespan and could have different clinical implications for pediatric and adult IBD forms.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117824"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SS-31@Fer-1 Alleviates ferroptosis in hypoxia/reoxygenation cardiomyocytes via mitochondrial targeting","authors":"Hao Zheng ,&nbsp;Jinbo Ou ,&nbsp;Hui Han ,&nbsp;Qizheng Lu ,&nbsp;Yunli Shen","doi":"10.1016/j.biopha.2025.117832","DOIUrl":"10.1016/j.biopha.2025.117832","url":null,"abstract":"<div><h3>Purpose</h3><div>Targeting mitochondrial ferroptosis presents a promising strategy for mitigating myocardial ischemia-reperfusion (I/R) injury. This study aims to evaluate the efficacy of the mitochondrial-targeted ferroptosis inhibitor SS-31@Fer-1 (elamipretide@ferrostatin1) in reducing myocardial I/R injury.</div></div><div><h3>Methods</h3><div>SS-31@Fer-1 was synthesized and applied to H9C2 cells subjected to hypoxia/reoxygenation (H/R) to assess its protective effects. Cytotoxicity was evaluated using a cell counting kit-8 (CCK-8) assay, with lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) levels measured. Mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were assessed using Mito-SOX and JC-1 fluorescent dyes, respectively. Lipid peroxidation products, malondialdehyde (MDA) and glutathione (GSH), were quantified. Mitochondrial structure, mt-cytochrome b (mt-Cytb), and mt-ATP synthase membrane subunit 6 (mt-ATP6) were analyzed. Additionally, iron homeostasis and ferroptosis markers were evaluated.</div></div><div><h3>Results</h3><div>SS-31@Fer-1 significantly improved H/R-induced cardiomyocyte viability and reduced LDH and CK-MB levels. Compared to the Fer-1 group, SS-31@Fer-1 reduced GSH and increased MDA levels, enhancing mitochondrial integrity and function. Notably, it increased mitochondrial ROS and decreased MMP, indicating a mitigation of H/R-induced cardiomyocyte cytotoxicity. Furthermore, SS-31@Fer-1 maintained cellular iron homeostasis, as evidenced by increased expression of FTH, FTMT, FPN, and ABCB8. Elevated levels of GPX4 and Nrf2 were observed, while ACSL4 and PTGS2 levels were reduced in the SS-31@Fer-1 group.</div></div><div><h3>Conclusions</h3><div>SS-31@Fer-1 effectively suppressed ferroptosis in H/R-induced cardiomyocytes by maintaining cellular iron homeostasis, improving mitochondrial function, and inhibiting oxidative stress. These findings provide novel insights and opportunities for alleviating myocardial I/R injury.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117832"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Doxorubicin and topotecan resistance in ovarian cancer: Gene expression and microenvironment analysis in 2D and 3D models","authors":"Monika Świerczewska ,&nbsp;Marta Nowacka ,&nbsp;Piotr Stasiak ,&nbsp;Dariusz Iżycki ,&nbsp;Karolina Sterzyńska ,&nbsp;Artur Płóciennik ,&nbsp;Michał Nowicki ,&nbsp;Radosław Januchowski","doi":"10.1016/j.biopha.2024.117804","DOIUrl":"10.1016/j.biopha.2024.117804","url":null,"abstract":"<div><div>This study explores the mechanisms underlying chemotherapy resistance in ovarian cancer (OC) using doxorubicin (DOX) and topotecan (TOP)-resistant cell lines derived from the drug-sensitive A2780 ovarian cancer cell line. Both two-dimensional (2D) monolayer cell cultures and three-dimensional (3D) spheroid models were employed to examine the differential drug responses in these environments. The results revealed that 3D spheroids demonstrated significantly higher resistance to DOX and TOP than 2D cultures, suggesting a closer mimicry of <em>in vivo</em> tumour conditions. Molecular analyses identified overexpression of essential drug resistance-related genes, including <em>MDR1</em> and <em>BCRP</em>, and extracellular matrix (ECM) components, such as <em>MYOT</em> and <em>SPP1</em>, which were more pronounced in resistant cell lines. <em>MDR1</em> and <em>BCRP</em> overexpression contribute to chemotherapy resistance in OC by expelling drugs like DOX and TOP. Targeting these transporters with inhibitors or gene silencing could improve drug efficacy, making them key therapeutic targets to enhance treatment outcomes for drug-resistant OC. The study further showed that EMT-associated markers, including <em>VIM</em>, <em>SNAIL1</em>, and <em>SNAIL2</em>, were upregulated in the 3D spheroids, reflecting a more mesenchymal phenotype. These findings suggest that factors beyond gene expression, such as spheroid architecture, cell-cell interactions, and drug penetration, contribute to the enhanced resistance observed in 3D cultures. These results highlight the importance of 3D cell culture models for a more accurate representation of tumour drug resistance mechanisms in ovarian cancer, providing valuable insights for therapeutic development.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"183 ","pages":"Article 117804"},"PeriodicalIF":6.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}