Frontiers in Pharmacology最新文献

{"title":"hERG activators exhibit antitumor effects in breast cancer through calcineurin and β-catenin-mediated signaling pathways.","authors":"Yan Yu, Chengchun Zhu, Xiao Wang, Ying Shi, Yiping Gao, Zhiyi Yu","doi":"10.3389/fphar.2025.1545300","DOIUrl":"10.3389/fphar.2025.1545300","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer remains a leading cause of mortality among women worldwide, with existing therapeutic options often accompanied by significant side effects and a persistent risk of disease recurrence. This highlights the need for novel drug candidates with new mechanisms of action by targeting alternative signaling pathways. While hERG channel is notoriously regarded as an off-target due to drug-induced cardiotoxicity, its therapeutic potential as a drug target remains largely unexplored.</p><p><strong>Methods: </strong>This study investigated the role of hERG in breast cancer progression and its impact on patient survival. The anti-proliferative, anti-migratory, anti-invasive and pro-apoptotic effects of hERG activators were evaluated using the Cell Counting Kit-8, wound healing assay, transwell assay and cell apoptosis assay, respectively. Western blotting, Ca²⁺ imaging and immunofluorescence assays were employed to study their antitumor mechanisms of actions.</p><p><strong>Results: </strong>We identified two novel hERG activators, <b>SDUY429</b> and <b>SDUY436</b>, which effectively inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells. In addition, <b>SDUY436</b> demonstrated significant anti-invasive and pro-apoptotic effects in MDA-MB-231 cells. Mechanistically, the anti-proliferative activity of hERG activators were mediated through calcineurin activation via enhanced calcium ion influx, which facilitated the nuclear translocation of nuclear factor of activated T cells (NFAT) and upregulated p21^Waf/Cip expression. Furthermore, both <b>SDUY429</b> and <b>SDUY436</b> remarkably suppressed the migration and invasion of MDA-MB-231 cells by downregulating the protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK3β)/β-catenin signaling pathway. The observed reduction in phospho-AKT-Ser473 (<i>p</i>AKT^S473) expression resulted in the decreased levels of phospho-GSK3β-Ser9 (<i>p</i>GSK3β^S9), thereby limiting the nuclear localization of β-catenin, which led to the inhibition of cell migration and invasion. Notably, combining <b>SDUY429</b> or <b>SDUY436</b> with the AKT inhibitor MK-2206 produced synergistic anti-proliferative effects.</p><p><strong>Conclusion: </strong>These findings suggest that hERG activators hold promise as new potential therapeutic agents for the treatment of breast cancer, paving the way for future investigations into their clinical applications.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1545300"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364315","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":"Modified citrus pectin ameliorates methotrexate-induced hepatic and pulmonary toxicity: role of Nrf2, galectin-3/TLR-4/NF-κB/TNF-α and TGF-β signaling pathways.","authors":"Randa Ismail, Heba A Habib, Aliaa F Anter, Amr Amin, Gehan H Heeba","doi":"10.3389/fphar.2025.1528978","DOIUrl":"10.3389/fphar.2025.1528978","url":null,"abstract":"<p><strong>Introduction: </strong>Methotrexate (MTX) is a frequently utilized anti-inflammatory and anticancer agent. Its potential liver and lung toxicity often limits its clinical effectiveness. We conducted this study to demonstrate the possible protective impacts of a natural galectin-3 (Gal-3) inhibitor, modified citrus pectin (MCP), against MTX-induced liver and lung toxicity and verify the potential signaling pathways of these suggested effects. <i>In vitro</i>, the cytotoxicity of MCP and its modulatory effect on MTX cytotoxic efficacy were assessed.</p><p><strong>Methods: </strong>Four groups of rats were used: control, MTX (40 mg/kg, single intraperitoneal injection on day 9), MTX + MCP (200 mg/kg/day, orally, for 2 weeks), and MCP alone. MCF7, Nalm6, and JEG3 cell lines were used for the <i>in vitro</i> cytotoxicity assay.</p><p><strong>Results: </strong>MCP counteracted liver and lung toxicity evidenced by ameliorating the markers of liver and lung functions. Moreover, MCP minimized oxidative stress elicited by MTX in lung and liver tissues, as indicated by reduced malondialdehyde levels, elevated levels of reduced glutathione, increased superoxide dismutase activity, and upregulated Nrf2 protein expression. In hepatic and pulmonary tissues, MCP downregulated the inflammatory signaling pathway, Gal-3/TLR-4/NF-κB/TNF-α. MCP pretreatment decreased TGF-β, collagen content, and cleaved caspase-3 levels. MCP enhanced the cytotoxicity of MTX in Nalm6 and JEG3 and did not interfere with its cytotoxicity in the MCF7 cell lines.</p><p><strong>Discussion: </strong>MCP attenuated MTX-induced liver and lung toxicity through antioxidant, anti-fibrotic, anti-inflammatory, and anti-apoptotic influences, as demonstrated by the improved histopathological changes induced by MTX in pulmonary and hepatic tissues. Moreover, it increased MTX cytotoxicity in different human cell lines.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1528978"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363829","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":"Comparison of a ready-to-use intranasal dexmedetomidine spray with traditional intranasal dexmedetomidine drops for sedation in preschool children: a prospective, randomized, controlled study.","authors":"Qi-Qi Jin, Wei-Cha Cai, Ying-Feng Zhou, Yan-Tong Zhang, Gang Chen, Meng-Ting Xu, Jun Li, Kai-Ming Yuan","doi":"10.3389/fphar.2025.1528612","DOIUrl":"10.3389/fphar.2025.1528612","url":null,"abstract":"<p><strong>Purpose: </strong>This study compared the efficacy and acceptability of a ready-to-use intranasal dexmedetomidine spray (DS) versus traditional drops administered by syringe (DD) in pediatric patients undergoing elective surgery.</p><p><strong>Patients and methods: </strong>Eighty-six preschool children were enrolled in a prospective, randomized, controlled study. Children were randomly assigned to receive either DS or DD. For children weighing between 10.5 and 18.5 kg, a dexmedetomidine dosage of 30 μg (two sprays) was administered, while those weighing between 18.5 and 25.5 kg received 45 μg (three sprays). In the DD group, dexmedetomidine was administered at a dose of 2 μg/kg based on body weight. The primary outcome was the proportion of children achieving a Ramsay sedation scale (RSS) score of ≥3 within 30 min. Secondary outcomes included acceptance of intranasal medication, anxiety at parental separation and prior to induction, and compliance with induction.</p><p><strong>Results: </strong>A total of 83 cases were analyzed. The proportion of children achieving an RSS score of ≥3 within 30 min was similar between the DS and DD groups (90.7% vs. 77.5%, respectively). However, the acceptance score was significantly better in the DS group (mean difference [95%]: -0.9 [-1.267 to -0.5325], P < 0.001). No significant differences were observed between the groups in terms of successful child-parent separation (88.4% vs. 85%) or satisfactory anxiolytic effect prior to induction (95.3% vs. 92.5%). Compliance with induction was comparable, with 53.5% in the DS group and 40.0% in the DD group demonstrating \"optimal\" compliance.</p><p><strong>Conclusion: </strong>Both intranasal spray and syringe drop methods were highly effective in providing sedation and anxiolysis, but the ready-to-use intranasal dexmedetomidine spray was more acceptable to children, offering a viable alternative to the syringe method.</p><p><strong>Clinical trial registration: </strong>ChiCTR.org.cn, identifier ChiCTR2400089374.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1528612"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364298","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: D-dencichine regulates thrombopoiesis by promoting megakaryocyte adhesion, migration and proplatelet formation.","authors":"Shilan Ding, Min Wang, Song Fang, Huibo Xu, Huiting Fan, Yu Tian, Yadong Zhai, Shan Lu, Xin Qi, Fei Wei, Guibo Sun, Xiaobo Sun","doi":"10.3389/fphar.2024.1504076","DOIUrl":"https://doi.org/10.3389/fphar.2024.1504076","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fphar.2018.00297.].</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1504076"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364214","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":"Real-world pharmacovigilance of ofatumumab in multiple sclerosis: a comprehensive FAERS data analysis.","authors":"Hui Chen","doi":"10.3389/fphar.2024.1521726","DOIUrl":"10.3389/fphar.2024.1521726","url":null,"abstract":"<p><strong>Background: </strong>Ofatumumab, a fully human monoclonal antibody targeting CD20, is approved for the treatment of relapsing multiple sclerosis. Comprehensive real-world safety data are crucial for informing clinical practice.</p><p><strong>Methods: </strong>The FDA Adverse Event Reporting System database was utilized to perform a disproportionality analysis, covering reports from Q3 2020 to Q2 2024, in which ofatumumab was identified as the primary suspected drug. Statistical approaches used included the Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Multi-item Gamma Poisson Shrinker. The timing of adverse events was assessed using the Weibull distribution model to highlight temporal risk patterns.</p><p><strong>Results: </strong>Known adverse reactions, such as injection site reactions and upper respiratory tract infections, displayed positive signals. Additionally, novel off-label adverse events, including brain fog, muscle spasms, and mood alterations, were identified, marking the first real-world evidence of these potential risks. Temporal analysis revealed that most adverse events occurred within the first month of treatment, indicating an early risk phase. Subgroup analysis demonstrated notable differences in adverse event profiles by gender and age, with males more prone to hyperhidrosis and older patients more susceptible to neurological symptoms.</p><p><strong>Conclusion: </strong>This real-world analysis of ofatumumab provides important safety insights, confirming known adverse reactions and identifying additional potential risks. Early and tailored monitoring protocols during the initial treatment phase, including regular neurological and psychiatric assessments, are recommended to optimize patient safety and outcomes. Prospective studies are recommended to validate these results and explore the underlying mechanisms.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1521726"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364196","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":"Fosaprepitant as combination therapy to prevent chemotherapy-induced vomiting in children: a meta-analysis.","authors":"Yanshuo Shi, Yuanyuan Yue, Yue Zhang, Guoxun Pang","doi":"10.3389/fphar.2025.1509928","DOIUrl":"10.3389/fphar.2025.1509928","url":null,"abstract":"<p><strong>Objective: </strong>To systematically evaluate the clinical efficacy and safety of fosaprepitant combined with 5-hydroxytryptamine 3 receptor antagonists (5-HT₃RA) (with or without dexamethasone) on the chemotherapy-induced vomiting in pediatric cancer patients.</p><p><strong>Methods: </strong>PubMed, Embase, Cochrane Library, China Journal full-text database (CNKI), Wanfang data knowledge service platform (Wanfang) and VIP Chinese sci-tech Journal full-text database (VIP) were searched by computer (retrieval time from database establishment to Apr. 2024), randomized controlled trials (RCTs) and cohort studies about fosaprepitant and 5-HT₃RA with or without dexamethasone (observation group) versus 5-HT₃RA, with or without dexamethasone, as the control group for chemotherapy-induced vomiting were collected, after data extraction and quality evaluation, meta-analysis was carried out by Rev Man 5.3 software.</p><p><strong>Results: </strong>A total of 731 patients were included in 7 trials. Meta-analysis results showed that the complete response (CCR, no vomiting/rescue medication) rates were higher in the observation group compared to that in the control group during the acute [the relative risk: RR = 1.64, 95% confidence interval: 95%CI = 1.35-1.99, P < 0.00001], delayed vomiting [RR = 2.05, 95%CI = 1.32-3.17, P = 0.001] and overall phases [RR = 2.08, 95%CI = 1.69-2.57, P < 0.00001], with statistical significance (P < 0.05). The subgroup analysis of salvage treatment proportion revealed that the need for rescue medication was higher for patients in the control than fosaprepitan regimens [RR = 0.20, 95%CI = 0.08-0.54, P = 0.001] There was no difference in the incidence of adverse drug reaction between two groups [RR = 0.95, 95%CI = 0.75-1.19, P = 0.66].</p><p><strong>Conclusion: </strong>Fosaprepitant in combination with 5-HT3RA (with or without dexamethasone) has the same safety and more effective in preventing chemotherapy-induced vomiting than 5-HT3RA with or without dexamethasone.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1509928"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364312","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":"Trazodone effectiveness in depression: impacts of trazodone extended release vs SSRIs on the health status and quality of life of patients with major depressive disorder.","authors":"Marcin Siwek, Adrian Andrzej Chrobak, Anna Julia Krupa, Aleksandra Gorostowicz, Andrzej Juryk, Dominika Dudek","doi":"10.3389/fphar.2024.1525498","DOIUrl":"10.3389/fphar.2024.1525498","url":null,"abstract":"<p><strong>Introduction: </strong>Early research on the pharmacotherapy for major depressive disorder (MDD) has largely focused on symptomatic improvements, whereas this focus has shifted to functioning and quality of life in recent years. Studies have confirmed that antidepressants generally improve the functional outcomes in MDD, but very few works have compared the efficacies of specific drugs. The present work aims to compare the impacts of trazodone once-a-day extended-release (XR) vs selective serotonin reuptake inhibitors (SSRIs) on the health status and quality of life in MDD.</p><p><strong>Methods: </strong>Data were gathered from 180 subjects through a naturalistic observation study of trazodone effectiveness in depression (TED) and analyzed. The TED study participants received trazodone XR of SSRIs in flexible doses for 12 weeks. The health status and health-related quality of life (HRQoL) were evaluated using the EQ-5D-5L tool at baseline as well as 2, 4, 8, and 12 weeks.</p><p><strong>Results: </strong>At baseline, the subjects treated with trazodone XR vs SSRIs presented similar health status profiles and HRQoL values with respect to the mobility, self-care, and anxiety/depression dimensions along with lower scores for the usual activities, pain/discomfort, overall HRQoL, and health status. Both trazodone XR and SSRIs improved the health status and HRQoL of the MDD patients at all subsequent timepoints. Compared to SSRIs, trazodone XR provided greater improvements in terms of the self-care, usual activities, pain/discomfort, and anxiety/depression measures and more often improved participant overall health status and HRQoL. More participants reported mixed changes in their health status and HRQoL in the SSRI group than the trazodone XR group.</p><p><strong>Discussion: </strong>Health status and HRQoL improved in both treatment arms, with preferable scores in trazodone XR vs. SSRIs group.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"15 ","pages":"1525498"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364201","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":"Regulation of Hippo-YAP1/TAZ pathway in metabolic dysfunction-associated steatotic liver disease.","authors":"Wei Xuan, Dandan Song, Jianghua Hou, Xiuping Meng","doi":"10.3389/fphar.2025.1505117","DOIUrl":"10.3389/fphar.2025.1505117","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide, but effective treatments are still lacking. Metabolic disorders such as iron overload, glycolysis, insulin resistance, lipid dysregulation, and glutaminolysis are found to induce liver senescence and ferroptosis, which are hot topics in the research of MASLD. Recent studies have shown that Hippo-YAP1/TAZ pathway is involved in the regulations of metabolism disorders, senescence, ferroptosis, inflammation, and fibrosis in MASLD, but their complex connections and contrast roles are also reported. In addition, therapeutics based on the Hippo-YAP1/TAZ pathway hold promising for MASLD treatment. In this review, we highlight the regulation and molecular mechanism of the Hippo-YAP1/TAZ pathway in MASLD and summarize potential therapeutic strategies for MASLD by regulating Hippo-YAP1/TAZ pathway.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1505117"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363840","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":"Itraconazole promotes melanoma cells apoptosis via inhibiting hedgehog signaling pathway-mediated autophagy.","authors":"Shunqiao Jin, Xiaojiao Liu, Lingqin Cai, Jiayu Yan, Ling Li, Hongjun Dong, Yuxue Gao, Xicong Zhu, Cong Zhang, Xuezhu Xu","doi":"10.3389/fphar.2025.1545243","DOIUrl":"10.3389/fphar.2025.1545243","url":null,"abstract":"<p><strong>Background: </strong>Itraconazole, a widely used antifungal medication, has shown potential in inhibiting tumor growth and reducing angiogenesis. However, its role in melanoma tumor growth remains insufficiently explored. This study investigates the inductive effect of itraconazole on autophagy-mediated apoptosis in melanoma cells.</p><p><strong>Method: </strong>Potential drug targets were identified using the PMF machine learning algorithm. Apoptosis and cell cycle in melanoma cell lines A375 and A2058 were assessed via flow cytometry. Western blot analysis was performed to examine autophagy and associated signaling proteins, while autophagy flux and autophagosome formation were visualized using fluorescence microscopy. A melanoma cell xenograft mouse model was established to evaluate the inhibitory mechanisms of itraconazole on tumor cell proliferation.</p><p><strong>Result: </strong>Using the PMF machine learning algorithm, SQSTM1 was identified as the primary target of itraconazole. Itraconazole inhibited melanoma cell proliferation by inducing G1 phase arrest and autophagy-mediated apoptosis in A375 and A2058 cells. Furthermore, itraconazole suppressed Hedgehog signaling and counteracted the activation of the Hedgehog agonist recombinant human Sonic Hedgehog (rhShh). <i>In vivo</i>, itraconazole significantly reduced tumor growth in A375 and A2058 xenograft models.</p><p><strong>Conclusion: </strong>Itraconazole induces autophagy-mediated apoptosis in melanoma cells by inhibiting Hedgehog signaling, underscoring its potential as a therapeutic option for melanoma treatment.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1545243"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364317","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":"Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: implications for the involvement of pirin.","authors":"Bardees M Foda, Annika E Baker, Łukasz Joachimiak, Marzena Mazur, Richard R Neubig","doi":"10.3389/fphar.2025.1505000","DOIUrl":"10.3389/fphar.2025.1505000","url":null,"abstract":"<p><strong>Aim: </strong>Overcoming therapy resistance is critical for effective melanoma control. Upregulation of Rho/MRTF signaling in human and mouse melanomas causes resistance to targeted therapies. Inhibition of this pathway by MRTFi, CCG-257081 resensitized resistant melanomas to BRAF and MEK inhibitors. It also prevented the development of resistance to vemurafenib (Vem). Here, we investigate the role of apoptosis and the protein pirin in CCG-257081-mediated suppression of drug resistance.</p><p><strong>Methods: </strong>Using naïve and resistant mouse YUMMER melanoma cells, we studied the effect of the BRAF inhibitor Vem with or without CCG-257081 on real-time growth and apoptosis (activation of caspase, Propidium iodide (PI) staining, and PARP cleavage). The effects of CCG-257081 on proliferation (Ki67) and caspase-3 activation were assessed in resistant YUMMER_R tumors <i>in vivo</i>. Finally, two CCG-257081 enantiomers were tested for pirin binding, inhibition of the Rho/MRTF-mediated activation of ACTA2 gene expression in fibroblasts, and the prevention of Vem resistance development by YUMMER_P cells.</p><p><strong>Results: </strong>Vem reduced growth of parental but not resistant cells, while CCG-257081 inhibited both. The combination was more effective than Vem alone. CCG-257081, but not Vem, induced activation of caspase-3 and -7 in resistant cells and increased PARP cleavage and PI staining. CCG-257081 reduced proliferation and activated caspase-3 in YUMMER_R melanoma tumors. Both CCG-257081 enantiomers robustly suppressed development of Vem-resistant colonies with the S isomer being more potent (1 μM IC₅₀).</p><p><strong>Conclusion: </strong>CCG-257081 appears to target pre-resistant cells and Vem-induced resistant cells through enhanced apoptosis. Inhibition of pirin or the Rho/MRTF pathway can be employed to prevent melanoma resistance.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1505000"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363639","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}