Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Clinical development of the GluN2B-selective NMDA receptor inhibitor NP10679 for the treatment of neurologic deficit after subarachnoid hemorrhage.","authors":"Haichen Wang, Raymond J Dingledine, Scott J Myers, Stephen F Traynelis, Chuan Fang, Yanli Tan, George W Koszalka, Daniel T Laskowitz","doi":"10.1124/jpet.124.002334","DOIUrl":"https://doi.org/10.1124/jpet.124.002334","url":null,"abstract":"<p><p>Aneurysmal subarachnoid hemorrhage (SAH) may be associated with cerebral vasospasm, which can lead to delayed cerebral ischemia, infarction, and worsened functional outcomes. The delayed nature of cerebral ischemia secondary to SAH-related vasculopathy presents a window of opportunity for the evaluation of well tolerated neuroprotective agents administered soon after ictus. Secondary ischemic injury in SAH is associated with increased extracellular glutamate, which can overactivate N-methyl-d-aspartate receptors (NMDARs), thereby triggering NMDAR-mediated cellular damage. In this study, we evaluated the effect of the pH-sensitive GluN2B-selective NMDAR inhibitor NP10679 on neurologic impairment after SAH. This compound demonstrates a selective increase in potency at the acidic extracellular pH levels that occur in the setting of ischemia. We found that NP10679 produced durable improvement of behavioral deficits in a well characterized murine model of SAH, and these effects were greater than those produced by nimodipine alone, the current standard of care. In addition, we observed an unexpected reduction in SAH-induced luminal narrowing of the middle cerebral artery. Neither nimodipine nor NP10679 alters each other's pharmacokinetic profile, suggesting no obvious drug-drug interactions. Based on allometric scaling of both toxicological and efficacy data, the therapeutic margin in humans should be at least 2. These results further demonstrate the utility of pH-dependent neuroprotective agents and GluN2B-selective NMDAR inhibitors as potential therapeutic strategies for the treatment of aneurysmal SAH. SIGNIFICANCE STATEMENT: This report describes the properties and utility of the GluN2B-selective pH-sensitive N-methyl-d-aspartate receptor inhibitor, NP10679, in a well characterized rodent model of subarachnoid hemorrhage. We show that the administration of NP10679 improves long-term neurological function following subarachnoid hemorrhage and that in rats, there are no drug-drug interactions between NP10679 and nimodipine, the standard of care for this indication.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100046"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074592","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":"Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.","authors":"Ahmed M Elshazly, Aya A Elzahed, David A Gewirtz","doi":"10.1124/jpet.123.002048","DOIUrl":"https://doi.org/10.1124/jpet.123.002048","url":null,"abstract":"<p><p>The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2 and, more recently, also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains their clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and nonprotective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome the development of resistance. SIGNIFICANCE STATEMENT: This manuscript is one in a series of papers that interrogate the role(s) of the autophagy induced in response to antineoplastic agents in various cancer models. This series of papers was developed in an effort to establish whether autophagy targeting or modulation is likely to be an effective adjuvant strategy to increase the efficacy of cancer chemotherapeutic agents. This review explores the relationship between the autophagic machinery and HER2-targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100007"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074645","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":"Quantification of cinpanemab (BIIB054) binding to α-synuclein in cerebrospinal fluid of phase 1 single ascending dose samples.","authors":"YuTing Liu, Minhua Yang, Kyle Fraser, Danielle Graham, Paul H Weinreb, Andreas Weihofen, Warren D Hirst, Jesse M Cedarbaum, Blake Pepinsky","doi":"10.1124/jpet.124.002199","DOIUrl":"https://doi.org/10.1124/jpet.124.002199","url":null,"abstract":"<p><p>Through its pathological and genetic association with Parkinson disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Although published studies from some immunotherapy trials have demonstrated engagement in plasma, none has shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system. Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low-affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels, plus its heterogeneous nature in cerebrospinal fluid (CSF), made it impossible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery electrochemiluminescence assay. CSF samples from healthy volunteers (HVs, n = 46) and individuals with PD (PD, n = 18) from study 228HV101 (phase 1 clinical trial of BIIB054) demonstrated dose- and time-dependent binding of cinpanemab to α-syn with measurable complexes detected at doses ≥15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 [HV], 0.8032 [PD] P < .0001 [HV, PD]). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. SIGNIFICANCE STATEMENT: A zero-length crosslinking method with Meso Scale Discovery detection was developed to enable quantification of cinpanemab-α-synuclein (α-syn) complexes in clinical cerebrospinal fluid samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding was consistent with cinpanemab's affinity for α-syn and provided confidence the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the central nervous system.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100003"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074831","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":"Innovation through imitation: IL-33 decoys show promise in pulmonary fibrosis.","authors":"Maya E Kotas, Erin D Gordon","doi":"10.1016/j.jpet.2024.100035","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100035","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100035"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074646","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":"Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.","authors":"Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu","doi":"10.1124/jpet.124.002424","DOIUrl":"https://doi.org/10.1124/jpet.124.002424","url":null,"abstract":"<p><p>Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100034"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074654","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":"Interrogating a compound library in search of an inhibitor for TREM-like transcript-1 to fibrinogen binding.","authors":"Andrea Acsiniuc, Barbara Manfredi, Javier Menéndez-Pérez, Siobhan Branfield, A Valance Washington","doi":"10.1124/jpet.124.002086","DOIUrl":"https://doi.org/10.1124/jpet.124.002086","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains one of the leading causes of death worldwide. Aberrant platelet function mediates fibrin(ogen)-rich thrombi that lead to occlusive thrombi associated with mortality. The receptor, TREM-like transcript-1 (TLT-1), stored in the platelet α-granules and released upon platelet activation, binds fibrinogen and von Willebrand factor. Once it is released from platelets, TLT-1 is a potential therapeutic target to prevent the thrombosis associated with CVD. Here we designed an assay to screen a compound library of small molecules inhibitors. Human embryonic kidney (HEK)-293 cells stably transfected with a full-length human treml-1 construct were used to screen library of 800 compounds, for inhibition of TLT-1 to fibrinogen binding in an attachment assay using crystal violet staining. The possible cytotoxicity of the best compounds was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide MTT and calcein AM staining assays. We demonstrated that the addition of TLT-1 to HEK-293 cells increases cell adhesion by more than 2-fold. We identified ∼80 compounds that inhibit binding by more than 80%. We further tested the top compounds and confirmed that reduction of hTLT-1 to fibrinogen bound in the top compounds was not caused by cytotoxicity, as per colorimetric and fluorescent viability assays. Four compounds were identified as potential small molecule inhibitors, one of which, BM-8372, demonstrated significant effect in platelet aggregation and spreading assays. SIGNIFICANCE STATEMENT: Triggering receptor expressed in myeloid cells-like transcript-1 (TLT-1) is a key platelet receptor that binds fibrinogen and mediates clot formation. The developed assay successfully screened 800 small molecules, pinpointing ∼80 potent inhibitors that reduce TLT-1 binding by over 80%. Importantly, the study rigorously rules out cytotoxicity concerns, affirming the therapeutic potential of the identified compounds. By elucidating TLT-1's role and presenting promising inhibitors, this research offers a significant stride toward developing novel strategies to combat cardiovascular disease-related thrombosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100009"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074650","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":"Mechanisms and management of thrombosis in cancer: Focus on gastrointestinal malignancies.","authors":"Simone Monegatti, Nicola Martinelli, Simonetta Friso, Henri M H Spronk, Hugo Ten Cate","doi":"10.1124/jpet.124.002203","DOIUrl":"https://doi.org/10.1124/jpet.124.002203","url":null,"abstract":"<p><p>Cancer patients have an increased risk of venous thromboembolism, which is their second cause of death after disease progression itself. Several thrombotic risk factors coexist in cancer patients, including the ability of both cancer and tumoral microenvironment's cells to directly or indirectly activate platelets and the enzymes of the coagulation cascade, resulting in a hypercoagulable state of blood. This narrative review gives an overview of the main mechanisms leading to venous thromboembolism in cancer patients, including the role that platelets and the clotting proteins may have in tumor growth and metastasis. Of note, the hemostatic balance is altered in cancer patients who may, next to a thrombosis tendency, also have an increased risk of bleeding. To highlight the complexity and the precariousness of the hemostatic balance of these patients, we discuss 2 specific gastrointestinal malignancies: hepatocellular carcinoma, which is frequently associated with liver cirrhosis, a condition that causes profound alterations of hemostasis, and colorectal cancer, which is characterized by a fragile mucosa that is prone to bleeding. Understanding the molecular mechanisms of cancer-associated thrombosis may give a unique opportunity to develop new innovative drugs, acting differently on distinct pathways and potentially allowing to reduce the risk of bleeding related to antithrombotic therapies. SIGNIFICANCE STATEMENT: The topic is significant because understanding the molecular mechanisms leading to cancer-associated thrombosis and bleeding, focusing on gastrointestinal malignancies, enables the development of more rationale and innovative antithrombotic strategies for cancer-associated thrombosis. Eventually, this will support an improved and patient-tailored antithrombotic management in vulnerable oncologic patients.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100018"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074652","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":"Discovery of aurovertin B as a potent metastasis inhibitor against triple-negative breast cancer: Elucidating the complex role of the ATF3-DUSP1 axis.","authors":"Jian-Jun Shen, Xi Yang, Meng Yu, Qing-Cui Li, Ru-Yu Wang, Wen-Yan Yu, Jia-Li Zhang, Yi-Li Chen, Wen-Ting Zhu, Jia Li, Zha-Jun Zhan, Rui Wu","doi":"10.1124/jpet.124.002264","DOIUrl":"https://doi.org/10.1124/jpet.124.002264","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is characterized by high mortality rates, primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937, and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of dual-specificity phosphatase 1 (DUSP1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified activating transcription factor 3 (ATF3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the metastatic mechanisms of TNBC. SIGNIFICANCE STATEMENT: This study constructs a high-throughput phenotypic screening system utilizing epithelial-mesenchymal transition marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100005"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074717","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":"Antidepressants for inflammatory bowel disease? Multimodal effects of amitriptyline in murine colitis.","authors":"Diane E Peters","doi":"10.1016/j.jpet.2024.103382","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.103382","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 3","pages":"103382"},"PeriodicalIF":3.1,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074578","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":"Humans and Rodents: The Case of hOAT4 and mOat5.","authors":"Pierantonio Menna, Emanuela Salvatorelli","doi":"10.1124/jpet.124.002307","DOIUrl":"10.1124/jpet.124.002307","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"391 3","pages":"375-377"},"PeriodicalIF":3.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676145","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}