Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Pleiotropic ligands at recombinant human targets retrieved from the PDSP K_i database: Comparative analysis of binding affinities, functional profiles, and screening of clinical relevance by therapeutic plasma concentrations.","authors":"Lilly Josephine Bindel, Roland Seifert","doi":"10.1016/j.jpet.2026.105030","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105030","url":null,"abstract":"<p><p>Pleiotropic ligands interact with multiple pharmacological targets, contributing to desired therapeutic but also adverse effects. This mini-review identifies pleiotropic compounds and integrates ligand binding affinities from the Psychoactive Drug Screening Program K_i database with target classification, therapeutic plasma concentrations, functional annotations from the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, and stereoisomer-specific comparisons. Compounds were included if potential target binding at recombinant human systems were reported for at least 10 targets (pK_i > 5). In total, 253 pleiotropic ligands were identified, including 72 approved drugs, 6 active metabolites, 2 endogenous ligands, and 170 research compounds. These ligands covered 4,447 relevant bindings, mainly at G-protein coupled receptors (GPCRs) (79.6%), followed by kinases (12.2%), transporters (6.5%), ion channels (1.7%), and other protein targets. The number of active targets ranged from 10 to 94, with a median of 14. GPCR binding was dominated by serotonin receptors (5-HT_xR), adrenoceptors (AR), and dopamine receptors (D_xR), whereas kinase-oriented ligands mainly showed intra-kinase pleiotropy. Therapeutic relevance screening of 74 approved drugs showed that the median number of potentially clinically relevant targets was 9 at the upper therapeutic concentration limit and 7 at the lower limit, indicating concentration-dependent target engagement in several compounds. Comparison with the IUPHAR/BPS Guide to Pharmacology showed both concordance with established targets but also found targets without curated annotations. The functional profile of mGPCR antagonists confirmed a broad GPCR target spectrum but differed in pK_i values and functional behavior. Stereoisomeric data were highly incomplete. Overall, pleiotropic ligand behavior is characterized by target breadth, affinity distribution, functional profile, and therapeutic context. SIGNIFICANCE STATEMENT: This analysis integrates binding affinities of pleiotropic ligands from the PDSP K_i data base with target classification, therapeutic plasma concentrations, and functional annotations from the IUPHAR/BPS Guide to Pharmacology. Target breadth, affinity distribution, functional behavior, and potential clinical relevance require consideration. For therapeutic compounds, established target annotations do not fully reflect the experimentally reported binding profile, and several non-primary targets may be clinically relevant.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105030"},"PeriodicalIF":4.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C5aR2 signaling mechanisms via the β-arrestin-dependent pathway observed in microsecond-scale molecular dynamics simulations.","authors":"Paulina Dragan, Dorota Latek","doi":"10.1016/j.jpet.2026.105028","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105028","url":null,"abstract":"<p><p>The complement system primarily regulates innate immunity, contributing to nonspecific antipathogen defense, and is linked to adaptive immunity. One of its components, C5 convertase, initiates the last stage of the complement cascade, leading to the cleavage of C5 into C5a and C5b and the formation of the membrane attack complex, which causes cell lysis. In addition, C5a acts as a proinflammatory mediator by regulating leukocyte chemotaxis. C5a binds to 2 G protein-coupled receptors: C5aR1 and C5aR2. C5aR1 activation is involved in inflammation through both G protein and β-arrestin-mediated signaling, while the effects of C5a binding to C5aR2 evoking only the β-arrestin signaling pathway are less defined. C5aR2, often considered a decoy receptor, exhibits both proinflammatory and anti-inflammatory effects in various disease models. To elucidate the physiological significance and therapeutic potential of C5aR2 signaling, we performed 4 μs-scale molecular dynamics simulations of the C5a-C5aR2-β-arrestin 1 complex starting from the active-state β-arrestin conformation. Two possible helix 8 (H8) conformations found in Protein Data Bank structures of C5aR1 used as templates for C5aR2 were tested. The canonical, outward-directed H8, lacking an amphipathic amino acid composition, untangled in all simulations. The noncanonical, inverted conformation of H8 remained stable in these 4-μs-long simulations, with a slight, incomplete clockwise rotation and the simultaneous outward movement of TM7, as observed in sweet-taste G protein-coupled receptors. Nevertheless, in both simulation systems, a short hydrophobic H8 fragment (LPAA) formed a stable anchor to the lipid bilayer throughout the 4-μs simulation. Based on our observations, we suggest that H8 could be limited to this short helical hydrophobic LPAA anchor that stabilizes the active-state β-arrestin conformation. These findings may explain the distinct, non-G protein-mediated signaling of C5aR2 compared with C5aR1 and provide insights into the 2 C5a-mediated signaling pathways, which exhibit significantly different therapeutic potential in the treatment of inflammatory diseases. SIGNIFICANCE STATEMENT: This extensive 4-μs-long, 6-replica molecular dynamics study provides important insights into the molecular basis of C5aR2 signaling, which can lead to either proinflammatory or anti-inflammatory effects, and could be exploited in the treatment of inflammatory diseases. To best of the authors' knowledge, it is the first study to present the molecular determinants of β-arrestin-biased signaling in the C5aR2 system. In addition, it elucidates the molecular mechanisms underlying β-arrestin-mediated signaling, focusing on its conformations and interactions with the receptor.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 11","pages":"105028"},"PeriodicalIF":4.3,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of pyruvate metabolism-related genes with immune infiltration and prognostic value in lung adenocarcinoma.","authors":"Fei Wang, Qiong Liang, Xiaotian Liang, Ying Liang, Qi Qin, Chaomian Yang","doi":"10.1016/j.jpet.2026.105027","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105027","url":null,"abstract":"<p><p>Pyruvate metabolism-related genes (PMRGs) play important roles in tumorigenesis and the tumor microenvironment. However, their prognostic value and biological relevance in lung adenocarcinoma (LUAD) remain unclear. LUAD transcriptomic, mutation, and clinical data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GSE31210 and GSE72094), and PMRGs from Kyoto Encyclopedia of Genes and Genomes. Differentially expressed PMRGs were identified by intersecting LUAD-related differentially expressed genes with PMRGs. Prognostic modeling, external validation, functional enrichment, immune infiltration, tumor mutation burden, and drug sensitivity analyses were performed. Based on PMRG expression, we established a 12-gene prognostic signature that effectively stratified patients with LUAD into high- and low-risk groups in The Cancer Genome Atlas training cohort and GSE72094 validation cohort. The Risk Score was confirmed as an independent prognostic factor for LUAD. Quantitative real-time reverse transcription PCR of 3 paired LUAD and adjacent normal tissues showed expression trends broadly consistent with bioinformatics results, but the small sample size precluded clinical validation. The low-risk group exhibited higher immune cell infiltration and potentially better immunotherapy responsiveness, whereas the high-risk group showed greater predicted sensitivity to bleomycin and doxorubicin. In vitro experiments further demonstrated that aldehyde dehydrogenase 1 family member B1 (ALDH1B1), a key signature gene, promoted LUAD cell proliferation, colony formation, migration, and invasion. Functionally, ALDH1B1 may enhance malignant phenotypes at least partially by activating glycolytic metabolism. These experiments provide preliminary, gene-specific functional evidence for ALDH1B1 but cannot be regarded as biological validation of the full 12-gene prognostic signature. Overall, this PMRG-related signature may possess prognostic stratification value for LUAD; however, its complete biological basis and clinical application potential require further verification. SIGNIFICANCE STATEMENT: A 12-gene pyruvate metabolism-related signature showed prognostic stratification value in retrospective LUAD cohorts and was associated with differences in immune profiles and predicted drug sensitivity. Functional experiments further provided preliminary evidence linking ALDH1B1 to malignant cellular phenotypes and glycolytic activity. Further prospective and functional validation of the complete signature is required.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105027"},"PeriodicalIF":4.3,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational pharmacokinetic/pharmacodynamic modeling to inform target concentration and dose projection of a novel selective estrogen receptor degrader (SIM0270) for early clinical development.","authors":"Yufei Shi, Meng Gu, Yang Yang, Shansen Xu, Qingfeng He, Peijin Li, Qi Fu, Chen Yang, Xiaoqiang Xiang, Jia Chen, Xiao Zhu","doi":"10.1016/j.jpet.2026.105025","DOIUrl":"https://doi.org/10.1016/j.jpet.2026.105025","url":null,"abstract":"<p><p>SIM0270 is a novel oral selective estrogen receptor degrader with high brain penetration and potent antitumor effects in preclinical studies. This study aimed to estimate target concentrations and project potentially clinically effective doses for early clinical development using an in silico translational pharmacokinetic (PK)/pharmacodynamic (PD) modeling approach. A translational PK/PD model was developed by integrating preclinical PK and PD data. The model incorporated a 1-compartment PK model with time-varying clearance for SIM0270, a turnover model with a capacity-limited inhibition effect of SIM0270-induced progesterone receptor (PR) downregulation, and tumor growth inhibition driven by PR reduction. SIM0270 concentrations in the tumor were 27.2 times higher than the paired plasma concentrations. The concentration for half of the maximum inhibitory effect was 17.4 ng/mL. The suppression of PR slows cancer progression, with half of the maximum tumor growth effect seen when normalized PR dropped to 0.576. Model-based simulations predicted that tumor stasis would occur at 17.4 ng/mL, whereas maximal tumor suppression would be approached at 22.7 ng/mL. Combination with palbociclib further enhanced tumor reduction by 42.7%. Accounting for penetration, simulations suggested that daily doses of 45 and 60 mg may correspond to tumor growth inhibition and near-maximal tumor suppression, respectively. These findings inform dose selection for early clinical development and highlight the value of translational PK/PD modeling in generating model-informed hypotheses for initial dose selection. SIGNIFICANCE STATEMENT: This study develops a translational pharmacokinetic/pharmacodynamic modeling framework for a novel oral selective estrogen receptor degrader that quantitatively links exposure to antitumor efficacy. Model-based simulations identify target concentrations for tumor stasis and maximal suppression, informing rational clinical dose selection. The iterative framework integrates nonclinical priors and adapts to emerging clinical data, improving decision-making across drug development.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 10","pages":"105025"},"PeriodicalIF":4.3,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149062053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial proteomic signatures of postcardiac arrest brain injury reveal potential therapeutic targets.","authors":"Yankang Ren, Xinhui Fan, Ping Gong, Xianfei Ji","doi":"10.1016/j.jpet.2026.105009","DOIUrl":"10.1016/j.jpet.2026.105009","url":null,"abstract":"<p><p>Mitochondrial dysfunction is central to postcardiac arrest brain injury (PCABI); however, the underlying protein networks involved remain poorly defined. SRT1720, a silent information regulator 1 activator, exhibits potential mitochondrial protective effects, although its role and mechanisms in PCABI are unclear. Adult male Wistar rats were randomized into sham, cardiopulmonary resuscitation (CPR), and SRT1720 groups and subjected to 8-minute asphyxia-induced cardiac arrest followed by CPR, with intraperitoneal SRT1720 (5 mg/kg) given 10 minutes after resuscitation. In a functional cohort (n = 15), SRT1720 significantly restored the mitochondrial calcium retention capacity, which was markedly impaired by cardiac arrest/CPR. Complex I activity was selectively suppressed and was restored by SRT1720, whereas other respiratory complex activities remained unchanged. In a parallel proteomic cohort (n = 9), 127 differentially expressed mitochondrial proteins were identified, with metabolic pathways being the most significantly enriched. Integrated network analysis revealed a coordinated pathological signature comprising complex I deficiency (NDUFB4), oxidative stress (NDUFB11), endoplasmic reticulum stress (RPN2), and lipid dysregulation (PLA2). SRT1720 treatment was associated with the reversal of these proteomic alterations and the re-establishment of metabolic homeostasis. Collectively, this multilevel analysis identifies a mitochondrial proteomic network disrupted in PCABI. The functional and proteomic recovery observed with SRT1720 is consistent with enhanced silent information regulator 1 signaling, suggesting a potential therapeutic strategy that warrants further mechanistic validation. SIGNIFICANCE STATEMENT: This study reveals a coordinated mitochondrial protein network-characterized by complex I dysfunction, oxidative stress, endoplasmic reticulum stress, and lipid dysregulation-as a key driver of postcardiac arrest brain injury. Treatment with the silent information regulator 1 activator SRT1720 was associated with the reversal of these proteomic alterations, selective restoration of complex I activity, and recovery of mitochondrial calcium regulation, thereby re-establishing energy metabolism and metabolic homeostasis. These integrated, multilevel findings provide a mechanistic framework for targeting mitochondrial dysfunction in postcardiac arrest brain injury and support SRT1720 as a promising therapeutic candidate.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105009"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CE9A215 (inotodiol) ameliorates oxazolone-induced atopic dermatitis by targeting mast cells and proinflammatory cytokines.","authors":"Thi Minh Nguyet Nguyen, Thi Thuong Do, Soyoung Ban, Su Been Hwang, Van Dinh Nguyen, Jong-Tae Park, Hyunjung Kim","doi":"10.1016/j.jpet.2026.104998","DOIUrl":"10.1016/j.jpet.2026.104998","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a chronic inflammatory skin disorder requiring long-term management; however, current therapeutics are often limited by side effects. CE9A215 (inotodiol), recently identified as a selective liver X receptor β agonist, has shown potential for regulating inflammation with a favorable safety profile. This study investigated the therapeutic efficacy and underlying mechanisms of CE9A215 in a murine model of oxazolone-induced chronic AD. We evaluated cellular responses using human mast cells (LUVA) and macrophages (RAW264.7) and assessed in vivo efficacy after oral administration of CE9A215 (4 and 10 mg/kg) for 9 days. In vitro, CE9A215 inhibited mast cell degranulation more effectively than dexamethasone and significantly suppressed lipopolysaccharide-induced proinflammatory cytokine production in macrophages. In vivo, CE9A215 treatment markedly ameliorated AD-like clinical symptoms, reducing epidermal hyperplasia to levels comparable to dexamethasone. Mechanistically, CE9A215 stabilized mast cells and macrophages within the dorsal skin, leading to significantly reduced levels of β-chymase in both serum and tissue. Furthermore, it downregulated the expression of key proinflammatory cytokines (tumor necrosis factor α and interleukin-1β) and T helper 2-associated cytokines (interleukin-4) in skin lesions. Notably, although systemic total IgE levels remained unchanged, the specific suppression of cutaneous interleukin-4 and inflammatory mediators indicates targeted regulation of the local inflammatory cascade. These findings suggest that CE9A215 alleviates AD pathology through liver X receptor β-mediated stabilization of mast cells and immune modulation, positioning it as a promising therapeutic candidate for chronic AD. SIGNIFICANCE STATEMENT: Current therapies for atopic dermatitis, including corticosteroids, are often limited by long-term side effects. This study identifies CE9A215 (inotodiol) as a potent therapeutic agent that ameliorates chronic atopic dermatitis pathology by targeting liver X receptor β. Unlike nonselective liver X receptor agonists known to induce hepatic steatosis, CE9A215 selectively stabilizes mast cells and macrophages without systemic toxicity.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104998"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of liver adverse events with nivolumab/ipilimumab combination therapy for hepatocellular carcinoma: A disproportionality analysis based on the Food and Drug Administration Adverse Event Reporting System data base.","authors":"Yujie Liu, Hao Yu, Yi Wang, Changjing Xu, Xuemei Liang, Kezhi Liu","doi":"10.1016/j.jpet.2026.104994","DOIUrl":"10.1016/j.jpet.2026.104994","url":null,"abstract":"<p><p>The combination of nivolumab and ipilimumab represents a major therapeutic advance for hepatocellular carcinoma (HCC), yet its real-world hepatic safety profile remains insufficiently characterized. To address this, we conducted a disproportionality analysis using adverse event reports from the US Food and Drug Administration Adverse Event Reporting System submitted between the first quarter of 2004 and the third quarter of 2025, specifically for patients with HCC receiving this dual immunotherapy. Disproportionality signals were assessed using 4 complementary methods: the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker. A total of 128 liver adverse event reports were identified, spanning 2 primary system organ classes with the majority classified under hepatobiliary disorders, and 5 significant disproportionality signals for specific liver adverse events were detected across these methods. Collectively, these findings highlight the critical need for vigilant monitoring of hepatic function in patients with HCC treated with nivolumab/ipilimumab in routine clinical practice. SIGNIFICANCE STATEMENT: The study specifically focuses on the hepatic safety of dual immune checkpoint inhibitor therapy in patients with HCC, addressing the gap in real-world hepatic safety data, and successfully identifies 5 specific liver adverse event signals that provide clear directions for clinical monitoring of liver injury.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104994"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNAs regulate the progression of pulmonary hypertension through distinct roles and mechanisms.","authors":"Gui-Feng Lu, Yao Guo, Fei Geng","doi":"10.1016/j.jpet.2026.104987","DOIUrl":"10.1016/j.jpet.2026.104987","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a progressive, life-threatening vascular disorder driven by pulmonary vascular remodeling and right ventricular dysfunction. Circular RNAs have emerged as key regulators of PH pathogenesis. In this review, we critically evaluate circular RNA expression profiles in clinical and experimental PH samples and synthesize their functional roles into 5 core pathogenic modules. The first 4 modules focus on pulmonary vascular cells (smooth muscle cells and endothelial cells): (1) transforming growth factor-β/bone morphogenetic protein receptor type-2 and phosphoinositide 3-kinase signaling; (2) noncanonical cell death (ferroptosis, pyroptosis, and autophagy); (3) epitranscriptomic, chromatin, and posttranslational regulation; and (4) metabolic reprogramming. The fifth module addresses (5) right ventricular remodeling. We also discuss their biomarker potential, therapeutic strategies, delivery challenges, and limitations. Collectively, this modular framework reveals that numerous dysregulated circular RNAs converge on limited shared pathways, underscoring their diagnostic and therapeutic potential in PH. SIGNIFICANCE STATEMENT: This review offers insights into circular RNA functions across key pathological processes of pulmonary hypertension, with the overall goal of identifying shared molecular pathways and developing them as novel biomarkers and therapeutic targets for this intractable vascular disorder.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104987"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RRx-001 sensitizes triple-negative breast cancer cells to oxaliplatin through apoptosis, cell cycle arrest, and immune modulation.","authors":"Rafid K Al-Fatlawi, Wrood S Al-Khfajy","doi":"10.1016/j.jpet.2026.104992","DOIUrl":"10.1016/j.jpet.2026.104992","url":null,"abstract":"<p><p>Triple-negative breast cancer is considered a highly aggressive type of breast cancer, for which there are few therapeutic options, and a very high level of resistance to chemotherapy. This research study has explored the synergistic anticancer effects of RRx-001 in combination with oxaliplatin on MDA-MB-231 cells. Cytotoxic effects were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Mechanistic studies were also conducted, including reactive oxygen species analysis, cell cycle analysis, colony formation assays, apoptosis assays, migration assays, and measurement of programmed death-ligand 1 expression by Western blotting. The results showed that RRx-001 was more effective than oxaliplatin after 24 hours (IC₅₀: 9.878 μM vs 202.2 μM). When RRx-001 was added to oxaliplatin, it produced a marked increase in cytotoxicity such that the effective IC₅₀ value for oxaliplatin was reduced by ∼10-fold. Moreover, the combination of RRx-001 + oxaliplatin resulted in increased generation of reactive oxygen species, caused S-phase arrest, reduced clonogenic survival, and increased apoptosis, as indicated by elevated levels of cleaved poly(ADP-ribose) polymerase-1. Further, RRx-001 diminished oxaliplatin's induction of programmed death-ligand 1 and significantly reduced cell migration. Collectively, these results demonstrate that RRx-001 has the ability to increase the efficacy of oxaliplatin through a number of synergistic mechanisms, and therefore may serve as a viable dose-sparing therapeutic option for patients with triple-negative breast cancer. SIGNIFICANCE STATEMENT: This study reports the discovery of RRx-001, a novel small molecule that enhances the activity of oxaliplatin. The use of this chemotherapy is diminished by the rapid emergence of resistance in tumor cells; this results in continued migration capability within tumor cells. RRx-001 addresses all oxaliplatin resistance mechanisms, and therefore may serve as an adjuvant therapeutic option for patients with triple-negative breast cancer.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"104992"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic mechanistic dominance in fentanyl and polysubstance overdose: Implications for next-generation reversal.","authors":"Michael Voronkov, George Milevich, John Abernethy","doi":"10.1016/j.jpet.2026.105002","DOIUrl":"10.1016/j.jpet.2026.105002","url":null,"abstract":"<p><p>High-potency synthetic opioids, such as fentanyl, now dominate the opioid crisis and are often mixed with other active substances. Naloxone, while essential, increasingly produces incomplete or transient reversal-not because the antagonist \"fails,\" but because respiratory depression reflects shifting mechanistic dominance rather than a single μ-opioid receptor pathway. The mechanism currently limiting ventilation-whether μ-opioid receptor, α₂-adrenergic, or other central nervous system depressant-determines both clinical trajectory and reversibility of the overdose. Preclinical, clinical, and forensic data indicate that polysubstance exposures can alter this dominant mechanism over time, creating pharmacokinetic-pharmacodynamic mismatches in which μ-antagonism alone may be insufficient. Viewing overdose as a sequence of pharmacokinetic-pharmacodynamic-driven state transitions provides a translational framework for intervention. We highlight pharmacologically grounded strategies to sustain ventilatory control, including optimized μ-antagonist dosing, ligand sequestration, α₂-directed adjuncts, and receptor-independent respiratory network modulation, and propose a dominance-centered framework for developing and prioritizing next-generation reversal approaches in mechanistically complex polysubstance overdoses. SIGNIFICANCE STATEMENT: Contemporary fentanyl and polysubstance overdoses often show incomplete or transient naloxone responses better explained by shifting mechanistic dominance and loss of compensatory reserve than by inadequate μ-opioid receptor blockade. This review organizes overdose into a few pharmacokinetic-pharmacodynamic-driven mechanistic states and asks which pathway actually limits ventilation. By mapping μ-antagonists, ligand sequestrants, α₂-directed adjuncts, and respiratory stimulants onto these states, it offers a mechanistically grounded way to prioritize next-generation reversal strategies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"393 9","pages":"105002"},"PeriodicalIF":4.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}