Biomedicine & Pharmacotherapy最新文献

{"title":"Two concurrent mechanisms are responsible for the INa increase produced by dapagliflozin and empagliflozin in healthy and heart failure cardiomyocytes","authors":"Josu Rapún ,&nbsp;Sara Pérez-Martín ,&nbsp;Anabel Cámara-Checa ,&nbsp;Gorka San José ,&nbsp;Roberto Núñez-Fernández ,&nbsp;Teresa Crespo-García ,&nbsp;Adam Hoban ,&nbsp;Marcos Rubio-Alarcón ,&nbsp;Elena Martínez-Blanco ,&nbsp;Juan Tamargo ,&nbsp;F. Javier Díez-Guerra ,&nbsp;Begoña López ,&nbsp;Ricardo Gómez ,&nbsp;Arantxa González ,&nbsp;Eva Delpón ,&nbsp;Ricardo Caballero","doi":"10.1016/j.biopha.2025.117984","DOIUrl":"10.1016/j.biopha.2025.117984","url":null,"abstract":"<div><div>Dapagliflozin and empagliflozin exert many cardiovascular protective actions in heart failure (HF) patients. HF-induced electrical remodelling decreases the expression of Nav1.5 channels (encoded by <em>SCN5A</em>) that generate the cardiac Na⁺ current (I_Na) impairing excitability and promoting arrhythmias. We aimed to mechanistically decipher the peak I_Na increase produced by dapagliflozin and empagliflozin in healthy and HF cardiomyocytes. We recorded macroscopic and single-channel currents and action potentials (AP) using the patch-clamp technique and generated a mouse model of HF with reduced ejection fraction by transverse aortic constriction (TAC). Single-channel recordings showed that dapagliflozin and empagliflozin (1 μM) increased the open probability (<em>P</em>_o) of Nav1.5 channels by augmenting channel re-openings and the number of traces with openings and by doubling the open time constant, respectively. Both drugs increased <em>SCN5A</em> mRNA levels and the membrane expression of Nav1.5 channels. Empagliflozin also enhanced the cytoplasmic mobility of Nav1.5 channels. Molecular modelling and site-directed mutagenesis analysis demonstrated that both drugs bind to a previously unknown site at the Nav1.5 DIII-DIV fenestration. Dapagliflozin and empagliflozin hyperpolarized the resting membrane potential and increased the action potential amplitude in human cardiomyocytes derived from induced pluripotent stem cells. Importantly, in TAC cardiomyocytes dapagliflozin and empagliflozin restored the HF-reduced peak I_Na to control levels. Dapagliflozin and empagliflozin bind to a novel site within cardiac Nav1.5 increasing I_Na by augmenting the <em>P</em>_o and the membrane expression of the channels. We hypothesized that this unique effects could be of interest for the treatment of arrhythmias associated with decreased Nav1.5 channel expression.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"186 ","pages":"Article 117984"},"PeriodicalIF":6.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637434","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":"Synergistic therapeutic efficacy of Selective Anticancer Complex in triple-negative breast cancer","authors":"Hye Min Cho ,&nbsp;Yeong Chae Ryu ,&nbsp;Jihee Park ,&nbsp;Byeong Hee Hwang","doi":"10.1016/j.biopha.2025.117983","DOIUrl":"10.1016/j.biopha.2025.117983","url":null,"abstract":"<div><div>This study introduces an innovative approach to treating incurable cancers, particularly triple-negative breast cancer, by developing a Selective Anticancer Complex (SAC). The SAC combines Cancer-Growth Inhibiting (CGI) siRNA with a novel Selective Anticancer Peptide (SAP), forming spontaneously through electrostatic attraction. This innovative complex not only enhances the stability and delivery efficiency of CGI siRNA but also exhibits a synergistic anticancer effect. Unlike traditional approaches where peptides serve merely as carriers or separate therapeutic agents, SAC integrates both delivery and therapeutic functions. The complex demonstrates remarkable selectivity, significantly reducing the viability of specific cancer cell lines like MDA-MB-231 while sparing normal cells. Animal studies corroborated these findings, showing statistically significant tumor size reduction in MDA-MB-231 xenografts. This research represents a significant advancement in cancer therapeutics, offering a safe and promising treatment option for triple-negative breast cancer, for which selective treatments are currently lacking. By successfully combining the gene-silencing capabilities of CGI siRNA with the anticancer properties of SAP, this study opens new avenues for designing multifunctional, selective anticancer therapies, potentially revolutionizing the approach to treating aggressive and resistant cancers.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117983"},"PeriodicalIF":6.9,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628237","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":"Chemotoxic and phototoxic effects of liposomal co-delivery of green synthesized silver nanoparticles and ZnPcS4 for enhanced photodynamic therapy in MCF-7 breast cancer cells: An in vitro study","authors":"Alexander Chota,&nbsp;Heidi Abrahamse,&nbsp;Blassan P. George","doi":"10.1016/j.biopha.2025.117986","DOIUrl":"10.1016/j.biopha.2025.117986","url":null,"abstract":"<div><div>Breast cancer remains a significant challenge in oncology, despite notable advances in treatment methods. Traditional therapies such as surgery, chemotherapy, radiation, and hormonal treatments have long been used to manage breast cancer. However, often patients experience treatment failure, resulting in disease recurrence and progression. Therefore, this study explores the therapeutic potential of green-synthesized silver nanoparticles (AgNPs), using the root methanol (MeOH) extract of the African medicinal plant <em>Dicoma anomala</em> (<em>D. anomala</em>) as a reducing agent, to combat breast cancer. AgNPs were synthesized using a bottom-up approach and later modified with liposomes (Lip) loaded with the photosensitizer zinc phthalocyanine tetrasulfonate (Lip@ZnPcS₄) through the thin film hydration method. Prior to <em>in vitro</em> cell culture studies, UV–Vis spectroscopy was used to study the <em>in vitro</em> drug release kinetics of nanoparticles (NPs) at pH 5.8 and 7.4 respectively. After a 24 h treatment period, MCF-7 breast cancer cells were evaluated for cell cytotoxicity using lactate dehydrogenase Cyto-Tox96® Non-Radioactive Cytotoxicity Assay Kit LDH and cell viability using the CellTiter-Glo® ATP luminescence assay kit. Cell death studies were analyzed using an inverted light microscope for morphological changes, fluorescence microscopy for reactive oxygen species (ROS) detection and Live/Dead cell viability, human p53 protein analysis using enzyme-linked immunosorbent assay (ELISA), apoptotic and anti-apoptotic protein analysis by immunofluorescence, and gene expression analysis using real-time reverse transcription polymerase chain reaction (RT-PCR) assay. The experiments were conducted in quadruplicate (n = 4), and the results were analyzed using IBM SPSS statistical software version 27, with a 95 % confidence interval. The synthesized NPs and nanocomplexes, including AgNPs, AgNPs-Lip, Lip@ZnPcS₄, and AgNPs-Lip@ZnPcS₄, demonstrated significant cytotoxicity and therapeutic potential against MCF-7 breast cancer cells. Notably, apoptosis was induced, primarily through the activation of the intrinsic pathway. Given the difficult prognosis associated with breast cancer, these findings highlight the promise of liposomal nanoformulations (NFs) in cancer photodynamic therapy (PDT), supporting further investigation in <em>in vivo</em> settings.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117986"},"PeriodicalIF":6.9,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628238","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":"Discussion of the material basis for prevention and treatment of pulmonary fibrosis using naturally medicinal and edible homologous herbs based on the dynamic process of Nrf2, NF-κB and TGF-β in PF","authors":"Yan Li ,&nbsp;Jia Zheng ,&nbsp;Fei Liu ,&nbsp;Xianfeng Tan ,&nbsp;Huiping Jiang ,&nbsp;Yongde Wang","doi":"10.1016/j.biopha.2025.117911","DOIUrl":"10.1016/j.biopha.2025.117911","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a progressive chronic lung disease with a high incidence and poor prognosis. Despite extensive research into the mechanisms that initiate and drive the progression of pulmonary fibrosis, developing effective treatments remains challenging due to the multiple etiologies, pathogenic links, and signaling pathways involved in PF. Indeed, nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa-B (NF-κB), and transforming growth factor-beta (TGF-β) are central players in the pathogenesis of pulmonary fibrosis, and each of these factors influences distinct yet interconnected processes that collectively contribute to disease progression: Nrf2 upregulates antioxidants to mitigate oxidative stress, NF-κB modulates inflammatory responses, and TGF-β promotes fibroblast activation and extracellular matrix (ECM) deposition, leading to fibrosis. Targeting these pathways may offer therapeutic strategies, uncover new insights and provide potential therapeutic targets for PF. Absolutely, the interactions between Nrf2, NF-κB, and TGF-β pathways are complex and can significantly influence the progression of PF, which indicated that targeting a single pathway may show poor efficacy in managing the condition. Moreover, few therapies that effectively intervene in these pathways have been approved. This review focused on the molecular mechanisms of Nrf2, NF-κB, and TGF-β involving in PF and the material basis of the naturally medicinal and edible homologous herbs, which provides a solid foundation for understanding the disease's pathogenesis, and supports the development of therapeutic drugs or treatments for addressing the complex nature of PF.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117911"},"PeriodicalIF":6.9,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628236","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":"KB-0118, A novel BET bromodomain inhibitor, suppresses Th17-mediated inflammation in inflammatory bowel disease","authors":"Yeo-Jin Jeong ,&nbsp;Yeon-Su Ok ,&nbsp;Gi-Nam Kwon ,&nbsp;Min-Young Kim ,&nbsp;Jin Hong Chun ,&nbsp;Sukmo Kang ,&nbsp;Haemi Yang ,&nbsp;Minhee Son ,&nbsp;In-hyun Lee ,&nbsp;Gi-Cheon Kim ,&nbsp;Ho-Keun Kwon","doi":"10.1016/j.biopha.2025.117933","DOIUrl":"10.1016/j.biopha.2025.117933","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) presents complex pathologies and remains challenging to treat, highlighting the urgent need for innovative therapeutics. This study evaluates KB-0118, a novel BET bromodomain inhibitor targeting BRD4, for its immunomodulatory effects in IBD. KB-0118 effectively inhibited pro-inflammatory cytokines, including TNF, IL-1β, and IL-23a, and selectively suppressed Th17 cell differentiation, a critical driver of IBD pathology. In both DSS-induced and T cell-mediated colitis models, KB-0118 significantly reduced disease severity, preserved colon structure, and lowered IL-17 expression. Mechanistic studies suggest KB-0118’s modulation of Th17-driven inflammation occurs through epigenetic suppression of BRD4, confirmed by transcriptomic analysis showing downregulation of STAT3 and BRD4 target genes. Compared to standard BET inhibitors like JQ1 and MS402, KB-0118 exhibited enhanced efficacy in restoring immune balance in IBD, positioning it as a promising therapeutic candidate for chronic inflammatory diseases. Further investigation into KB-0118’s specificity and long-term effects will be essential to clarify its full clinical potential.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117933"},"PeriodicalIF":6.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619208","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":"Effect of hexyloxy position on antagonistic properties of KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) at muscarinic acetylcholine receptors","authors":"Alena Janoušková-Randáková ,&nbsp;Eva Mezeiová ,&nbsp;Jana Bláhová ,&nbsp;Nikolai Chetverikov ,&nbsp;Eva Dolejší ,&nbsp;Dominik Nelic ,&nbsp;Lukáš Prchal ,&nbsp;Martin Novák ,&nbsp;Jan Korábečný ,&nbsp;Jan Jakubík","doi":"10.1016/j.biopha.2025.117977","DOIUrl":"10.1016/j.biopha.2025.117977","url":null,"abstract":"<div><div>Antagonists with a long residence time at the receptors are desired for the possibility of reducing daily doses and side effects. KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) is the long-acting M₁-preferring bitopic muscarinic antagonist with a half-life at muscarinic receptors of up to five hours. The binding of 2-hexyloxy and 3-hexyloxy analogues of KH-5 was simulated <em>in silico</em>, compounds were synthesized and their binding and antagonistic properties were measured experimentally in CHO cells expressing individual subtypes of muscarinic acetylcholine receptors. The overall binding affinities of the new compounds were similar to their respective parent compounds. Shifting the hexyloxy chain to <em>ortho</em> and <em>meta</em> positions led to a decrease in potency at the M₁ receptor but an increase in potency at the M₂ receptor and abolition of long-term antagonism. Preservation of the <em>para</em> position of the hexyloxy chain is essential for the further development of M₁-preferring antagonists. Modifications of the basic centre may be the way to improve the geometry of antagonists towards long residence times to obtain the desired long-acting muscarinic antagonists in the future. The additional challenge for further development is the low metabolic stability of compounds.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117977"},"PeriodicalIF":6.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619219","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":"Sodium-glucose co-transporters (SGLT2) inhibitors prevent lipid droplets formation in vascular inflammation or lipid overload by SGLT2-independent mechanism","authors":"Natalia Chorazy ,&nbsp;Kamila Wojnar-Lason ,&nbsp;Anna M. Gdula ,&nbsp;Diane Bakker ,&nbsp;Coert J. Zuurbier ,&nbsp;Stefan Chlopicki ,&nbsp;Marta Z. Pacia","doi":"10.1016/j.biopha.2025.117967","DOIUrl":"10.1016/j.biopha.2025.117967","url":null,"abstract":"<div><h3>Background</h3><div>The formation of vascular lipid droplets (LDs) induced by vascular inflammation or lipid overload contributes to vascular pathophysiology in diabetes and cardiometabolic diseases, while sodium-glucose co-transporter 2 inhibitors (SGLT2-I) are beneficial in treating these conditions. Thus, we hypothesized that SGLT2-I would directly modify vascular LDs formation during vascular inflammation or lipid overload, and explored underlying mechanisms.</div></div><div><h3>Methods</h3><div>LDs formation in isolated murine aorta from wild-type or SGLT2-KO animals was induced by either treatment with tumour necrosis factor (TNF) to induce vascular inflammation or using oleic acid (OA) to mimic lipid overload. Vascular LDs and markers of vascular inflammation were monitored through fluorescence microscopy. Pharmacological inhibitors of sodium-hydrogen exchanger 1 (NHE1), endothelial sodium channels (EnNaC), sodium-calcium exchanger (NCX), protein kinase C (PKC), and NOX1/4 were used to test their role in empagliflozin’s effects on vascular LDs.</div></div><div><h3>Results</h3><div>Empagliflozin, dapagliflozin or ertugliflozin inhibited LDs formation in aorta exposed to TNF or OA. Empagliflozin reduced vascular inflammation (based on ICAM-1) and TNF/OA-induced LDs formation. These effects persisted in SGLT2-KO mice. Inhibition of NHE1, PKC or NOX1/4 recapitulated empagliflozin’s effects on TNF-induced vascular inflammation, without additional effects of empagliflozin. However, NHE1 inhibition was not involved in the SGLT2-independent reduction of OA-induced LDs formation by empagliflozin.</div></div><div><h3>Conclusions</h3><div>This is the first report demonstrating that SGLT2-I prevent the formation of LDs in the vasculature. Empagliflozin downregulates LDs formation in vascular inflammation or lipid overload <em>via</em> an SGLT2-independent mechanism. Empagliflozin’s protective effects involve the NHE1/PKC/NOX pathway in the TNF response but not in the OA response.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117967"},"PeriodicalIF":6.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619218","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 keratinocyte proliferation and differentiation by secoiridoid oleacein in monoculture and fibroblast co-culture models","authors":"Juhee Cho ,&nbsp;Meriem Bejaoui ,&nbsp;Hiroko Isoda","doi":"10.1016/j.biopha.2025.117985","DOIUrl":"10.1016/j.biopha.2025.117985","url":null,"abstract":"<div><div>Aberrant differentiation of keratinocytes is closely associated with both pathological skin disorders and non-pathological skin conditions, making the maintenance of normal differentiation process essential for skin integrity and homeostasis. This study investigated the effect of olive-derived secoiridoid oleacein (OC) on keratinocyte proliferation and differentiation <em>in vitro</em> and further validated it in a co-culture model with fibroblasts mimicking a skin-like environment. OC was compared with oleuropein (OP) as a reference compound having similar chemical structure and reported effects on skin barrier formation and wound healing. Notably, OC significantly increased the proliferation makers <em>KRT5</em> and <em>KRT14</em> and demonstrated wound healing effect under low-calcium condition, reflecting characteristics of the basal layer. Under high-calcium condition, OC markedly upregulated differentiation markers <em>KRT10</em>, <em>IVL</em>, <em>FLG</em>, and <em>TGM1</em>, along with differentiation characteristics such as cytoplasmic extensions and cell adhesion. Transcriptomic analysis revealed that OP and OC shared a common upstream pathway, Integrin/E-cadherin-Rho-MAPK, at the cytoplasm, while they showed distinct regulatory mechanisms within the nucleus. OP induced differentiation by suppressing stemness genes through epigenetic regulation, whereas OC secured differentiation stability by suppressing proliferative gene <em>ESR1</em> and activating the DNA damage response from DNA damage or mechanical stress occurring during differentiation. Our study is the first to elucidate the dual regulatory effects of OC on keratinocyte proliferation and differentiation stage-dependently as well as its underlying molecular mechanisms, suggesting that the divergent regulatory mechanisms may be due to their structural differences. These findings highlight OC as a skin protective agent for maintaining skin health and suggest its therapeutic potential for skin disorders related to abnormal differentiation.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117985"},"PeriodicalIF":6.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619089","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 “A novel missense mutation Smad4 V354L enhances the efficacy of docetaxel in non-small cell lung cancer” [Biomed. Pharmacother. 184 (2025) 117899]","authors":"Xia Xue ,&nbsp;Yongjia Zhou ,&nbsp;Huiping Liu ,&nbsp;Yan Gao ,&nbsp;Xinyu Ma ,&nbsp;Zhaohua Xiao ,&nbsp;Wenhao Zhang ,&nbsp;Peichao Li ,&nbsp;Zhongxian Tian ,&nbsp;Yun Luan ,&nbsp;Xiaogang Zhao","doi":"10.1016/j.biopha.2025.117970","DOIUrl":"10.1016/j.biopha.2025.117970","url":null,"abstract":"","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117970"},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631121","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":"Deciphering the mechanisms of PARP inhibitor resistance in prostate cancer: Implications for precision medicine","authors":"Cheng Wang ,&nbsp;Xiaoran Han ,&nbsp;Shaoqiu Kong ,&nbsp;Shanhua Zhang ,&nbsp;Hao Ning ,&nbsp;Fei Wu","doi":"10.1016/j.biopha.2025.117955","DOIUrl":"10.1016/j.biopha.2025.117955","url":null,"abstract":"<div><div>Prostate cancer is a leading malignancy among men. While early-stage prostate cancer can be effectively managed, metastatic prostate cancer remains incurable, with a median survival of 3–5 years. The primary treatment for advanced prostate cancer is androgen deprivation therapy (ADT), but resistance to ADT often leads to castrationresistant prostate cancer (CRPC), presenting a significant therapeutic challenge. The advent of precision medicine has introduced promising new treatments, including PARP inhibitors (PARPi), which target defects in DNA repair mechanisms in cancer cells. PARPi have shown efficacy in treating advanced prostate cancer, especially in patients with metastatic CRPC (mCRPC) harboring homologous recombination (HR)-associated gene mutations. Despite these advancements, resistance to PARPi remains a critical issue. Here, we explored the primary mechanisms of PARPi resistance in prostate cancer. Key resistance mechanisms include homologous recombination recovery through reverse mutations in BRCA genes, BRCA promoter demethylation, and non-degradation of mutated BRCA proteins. The tumor microenvironment and overactivation of the base excision repair pathway also play significant roles in bypassing PARPi-induced synthetic lethality. In addition, we explored the clinical implications and therapeutic strategies to overcome resistance,emphasizing the need for precision medicine approaches. Our findings highlight the need for comprehensive strategies to improve PARPi sensitivity and effectiveness,ultimately aiming to extend patient survival and improve the quality of life for those with advanced prostate cancer. As our understanding of PARPi resistance evolves, more diverse and effective individualized treatment regimens will emerge.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"185 ","pages":"Article 117955"},"PeriodicalIF":6.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619207","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}