syrosingopine / Generic mfg. - LARVOL DELTA

The Monocarboxylate Transporters MCT1 and MCT4 Are Highly Expressed in Glioblastoma and Crucially Implicated in the Pathobiology. (PubMed, Neuropathology) - "The results indicated the role of MCT1/4 in the pathobiology of GBM and the diagnostic utility at the immunohistochemical level. Syrosingopine, an antihypertensive agent with good CNS penetration and previously used in different malignancies, may be an essential therapeutic adjunct in GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Metabolic Disorders • Oligodendroglioma • Oncology • Solid Tumor • SLC16A1

Repurposing brucine as a chemopreventive agent in mammary gland carcinoma: Regulating lactate transport through MCT-4. (PubMed, Toxicol Rep) - "Syrosingopine (SRY) is a well-established inhibitor of lactate transport through MCT-4...BRU demonstrated significant cytotoxicity and increased the extracellular lactate levels in MCF-7 cells. The findings strongly encouraged BRU's effectiveness, offering promising paths for subsequent investigations."

Journal • Breast Cancer • Cardiovascular • Hypertension • Oncology • Solid Tumor

Post-ischemic inactivation of HIF Prolyl Hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis. (PubMed, J Clin Invest) - "Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair in PHDTiEC mice. Mechanistically, MCT4 inhibition suppressed pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • SLC16A3

HLA is a potent immunoinflammatory target in asymptomatic Alzheimer's disease. (PubMed, Neuroscience) - "Five FDA-approved drugs (Itrazole, Dfo, Syrosingopine, Cefoperazone and Pradaxa) were predicted as the common drug-targeted HLA-C and HLA-DRB1 by molecular docking. Taken together, the changes in the immune microenvironment of asymptomatic AD, and provided a new perspective for the development of anti-inflammatory drugs for AD early treatment."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • HLA-C • HLA-DRB1 • IL6 • TGFB1

Mitochondrial-uncoupling nanomedicine for self-heating and immunometabolism regulation in cancer cells. (PubMed, Biomaterials) - "Herein, a CD44-targeted and thermal-responsive nanocarrier was developed for the simultaneous delivery of 2,4-dinitrophenol and syrosingopine...The synergistic effects of endogenous hyperthermia and immunometabolism regulation by this nanomedicine have potential to enhance tumor immunogenicity, reshape the tumour immune microenvironment, and effectively suppress the growth of subcutaneous tumours and patient-derived organoids in triple-negative breast cancer. Therefore, the endogenous hyperthermia strategy developed in this study would revolutionize hyperthermia for cancer treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Additionally, we found that intracellular alkalization and extracellular acidification occur in PASMC following CH, and in vitro hypoxia, which was prevented by inhibition of glycolysis with 2-deoxy-D-glucose (2-DG)...Although the putative monocarboxylate transporter 1 (MCT1) and -4 (MCT4) inhibitor, syrosingopine, prevented the pH shift; the specific MCT1 inhibitor, AZD3965, and/or the MCT4 inhibitor, VB124, were without effect, suggesting syrosingopine targets the glycolytic pathway independent of H+ export...These data suggest multiple H+ transport mechanisms contribute to extracellular acidosis and inhibiting glycolysis, rather than specific H+ transporters, more effectively prevents extracellular acidification and ASIC1a activation. Together, these data reveal a novel pathologic relationship between glycolysis and ASIC1a activation in hypoxic PHTN."

Journal • Cardiovascular • Hypertension • Metabolic Disorders • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CA9 • SLC16A1

Syrosingopine and UK5099 synergistically suppress non-small cell lung cancer by activating the integrated stress response. (PubMed, Cell Death Dis) - "Importantly, our findings suggested that the synergistic suppression of NSCLC by syrosingopine and UK-5099 was dependent on ISR activation. In summary, our study proposed a promising therapeutic approach that involved the combination of Syrosingopine and UK-5099 to activate ISR, significantly hindering NSCLC growth and proliferation."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

INFLUENCE OF A PROINFLAMMATORY ENVIRONMENT ON THE EXPRESSION OF RECEPTORS OR TRANSPORTERS OF THE METABOLITES LACTATE AND SUCCINATE IN PATHOPHYSIOLOGICAL EFFECTOR CELLS IN RHEUMATOID ARTHRITIS (EULAR 2024) - "LPS-stimulated RASF were additionally treated with chemical inhibitors against MCT1 (AZD3965) and MCT4 (syrosingopine, preferential MCT4 inhibitor). A proinflammatory environment appears to differentially affect the expression of the transporters or receptors of lactate and succinate depending on the cell type and the proinflammatory factor. The increased MCT4 expression of RASF in comparison to SF of osteoarthritis patients might at least partially be caused by alterations of systemic LPS levels. The application of chemical MCT inhibitors is probably not suited for suppressing the LPS-induced IL-6 secretion of RASF."

Immunology • Inflammatory Arthritis • Osteoarthritis • Pain • Rheumatoid Arthritis • Rheumatology • CXCR3 • IL1B • IL6 • SUCNR1 • TNFA

Syrosingopine, an anti-hypertensive drug and lactate transporter (MCT1/4) inhibitor, activates hepatic stellate cells and exacerbates liver fibrosis in a mouse model. (PubMed, Genes Dis) - No abstract available

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis

AC-73 and Syrosingopine Inhibit SARS-CoV-2 Entry into Megakaryocytes by Targeting CD147 and MCT4. (PubMed, Viruses) - "Importantly, we found that AC-73 or syrosingopine significantly inhibits SARS-CoV-2 infection of megakaryocytes. Altogether, our data indicate AC-73 and syrosingopine as inhibitors of SARS-CoV-2 infection via CD147 and MCT4 that can be used to prevent SARS-CoV-2 binding and entry into megakaryocytes, which are precursors of platelets involved in COVID-19-associated coagulopathy."

Journal • Hematological Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • BSG • CD34

Syrosingopine Enhances 20S Proteasome Activity and Degradation of α-Synuclein. (PubMed, J Nat Prod) - "Among them, syrosingopine was the most potent activator of the 20S proteasome and enhanced the degradation of fluorogenic substrates and α-synuclein, an IDP. Furthermore, in HeLa cells, syrosingopine enabled the binding of a membrane-permeable fluorescent probe to the catalytic site of the 20S proteasome by opening the gate."

Journal • CNS Disorders • Targeted Protein Degradation

A COMPARATIVE ANALYSIS OF METABOLIC FLEXIBILITY IN OSTEOSARCOMA CELLS (CTOS 2023) - "We later tested the effects of lactate transport inhibition with monocarboxylate transporters MCT1 +/- MCT4 inhibitors AZD3965 and syrosingopine in combination with carboplatin chemotherapy, and found that syrosingopine, but not AZD3965 significantly reduced cell viability. Collectively, our results suggest that coordinate regulation of lactate metabolism in OS fulfills a metabolic gap in respiration to assist in aerobic cancer survival, and that targeted metabolic inhibitors may synergise with chemotherapy. Furthermore, metastatic OS cells appear to be more energetic and energetically flexible than primary OS cells and mesenchymal cells. Together, these and future investigations into the metabolic landscape of OS may lead to future clinical applications for OS patients."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Endothelial Cells Regulate Post-Ischemic Kidney Repair Through PHD/HIF-Dependent Hyperglycolysis (KIDNEY WEEK 2023) - "Ischemia-reperfusion injury (IRI) was induced by uni-/bilateral renal artery clamping, and tamoxifen treatment was started at day 1 post IRI, followed by analysis at day 14. Compared to Cre- controls, day 14 post IRI kidneys of PHD TiEC showed significant upregulation of profibrotic genes Loxl2, Tgfβ1, and Acta2, increased collagen deposition (n=6-8, p≤0.05), higher tubular injury, and reduced capillary density...Notably, post-ischemic administration of the dual MCT4/MCT1 inhibitor Syrosingopine (Syro) attenuated kidney injury in PHD TiEC mice (n=4, P≤0.5). In summary, endothelial PHDs regulate post-ischemic kidney repair through HIF-dependent mechanisms. Furthermore, our studies identify the endothelial MCT4 as a potential target for renoprotective therapies."

Acute Kidney Injury • Cardiovascular • Fibrosis • Immunology • Nephrology • Renal Disease • Reperfusion Injury • ACTA2 • CDH5 • ICAM1 • SLC16A3 • TGFB1 • VCAM1

An engineered nanoplatform cascade to relieve extracellular acidity and enhance resistance-free chemotherapy. (PubMed, J Control Release) - "The P-S-Z NPs selectively accumulate in tumors and then regulate the release of S-Z NPs containing syrosingopine (Syr) and acid-activated prodrug ZMC1-Pt depending on the extracellular acidity...As a proof of concept, this is a promising strategy to transfer the adverse effect of intracellular acidosis to facilitate chemotherapy. This well-designed delivery system effectively kills tumor cells without causing significant tumor drug resistance, thus opening a new window to treat cancer."

Journal • Metabolic Disorders • Oncology

Evaluating [F]FDG and [F]FLT Radiotracers as Biomarkers of Response for Combined Therapy Outcome in Triple-Negative and Estrogen-Receptor-Positive Breast Cancer Models. (PubMed, Int J Mol Sci) - "A typical feature of BC cells is the metabolic shift toward increased glycolysis, which has become an interesting therapeutic target for metabolic drugs such as metformin (MET). Recently, the administration of the antihypertensive syrosingopine (SYRO) in combination with MET has shown a synergistic effect toward a variety of cancers...The study provides evidence that SYRO plus MET has a synergistic effect on tumor growth inhibition in both 4T1 and TS/A experimental models and has showed the highest efficacy on the TNBC xenograft mice (4T1) via the expression reduction in the lactate transporter MCT4 and in the epithelial-mesenchymal transition biomarker Snail, promoting its potential application in therapy settings. In addition, the selective reduction in the [F]FLT tumor uptake (at 7 dd), observed in the SYRO plus MET treated mice in comparison with the vehicle group, suggests that this radiotracer could be potentially used as a biomarker for the early detection of..."

Biomarker • Journal • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER

Lactate Efflux Inhibition by Syrosingopine/LOD Co-Loaded Nanozyme for Synergetic Self-Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling. (PubMed, Adv Sci (Weinh)) - "Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof-of-concept study represents a promising candidate nanoplatform for synergetic cancer treatment."

Journal • Oncology

An acid test for metformin. (PubMed, J Pathol) - "The identification of syrosingopine as an inhibitor of the lactate transporters monocarboxylate transporter (MCT) 1 and the tumor-induced isoform MCT4 suggests a potential therapeutic intervention."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Targeting MCT1-mediated Intercellular Lactate Shuttling Attenuates Pulmonary Fibrosis (ATS 2023) - "Wildtype mice were exposed to bleomycin and were treated with syrosingopine, an anti-hypertensive medication which can inhibit MCT1 activity. Fibroblast-derived lactate modulates macrophage profibrotic polarization in pulmonary fibrosis. MCT1 mediates lactate intercellular shuttling and inhibiting MCT1 can attenuate fibrosis in vivo. Research"

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • MCT1

Mechanism Underlying Lactate-induced Effect On Monocytes In An Exercise Context (ACSM 2023) - "For transporter inhibition, monocytes were pre-treated with 100 nM AR-C155858 (inhibits MCT1), 10 uM syrosingopine (inhibits MCT1 and MCT4), or media for 15 min before lactate treatment... Physiologically-relevant lactate concentrations suppress glycolytic activation and inflammation in monocytes treated with S1. Inhibition of MCT1 may not inhibit lactate uptake due to redundancy with MCT4. Dual inhibition of MCT1/4 may substantially reduce ECAR due to the buildup of endogenous lactate."

Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

HTLV-1 bZIP factor-induced reprogramming of lactate metabolism and epigenetic status promote leukemic cell expansion. (PubMed, Blood Cancer Discov) - "An MCT1/4 inhibitor, syrosingopine, decreases the growth of ATL cells in vitro and in vivo. MCT1/4 expression is positively correlated with TAp73 in many cancers, and MCT1/4 upregulation is associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to cancer metabolism."

Journal • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BATF3 • IRF4 • MCT1

MCT inhibition resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide (AUA 2023) - "We treated C4-2B and 22Rv1 parental and enzalutamide-resistant cells with varying concentrations of MCT inhibitors AR-C155858, AZD3965, or syrosingopine either singly or in combination with enzalutamide and assessed cell survival, cell viability, proliferation, clonogenic ability, survival in 3-D models, and glycolytic activity. MCT activation may underlie the development of enzalutamide resistance in PCa and targeting it may represent a viable combinatorial option."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Heterostructural Nanoadjuvant CuSe/CoSe for Potentiating Ferroptosis and Photoimmunotherapy through Intratumoral Blocked Lactate Efflux. (PubMed, J Am Chem Soc) - "Herein, an activatable immunomodulatory nanoadjuvant CuSe/CoSe@syrosingopine (CSC@Syro) is constructed for simultaneously relieving immunosuppressive TME and boosting tumor immune response...Hence, advanced metabolic modulation confers the potentiated immune infiltration of ICD-stimulated T lymphocytes and further reinforces antitumor therapy. In brief, CSC@Syro-mediated synergistic therapy could elicit potent immunogenicity and suppress tumor proliferation and metastasis effectually by integrating the tumor metabolic regulation and ferroptosis with immunotherapy."

IO biomarker • Journal • Immune Modulation • Oncology • Solid Tumor

Metformin confers sensitization to syrosingopine in Multiple Myeloma cells by metabolic blockage and inhibition of protein synthesis. (PubMed, J Pathol) - "Finally, the combination treatment resulted in a significant reduction in tumour burden in vivo. This study proposes an alternative combination treatment for MM and provides insight in the intracellular effects."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • MCT1

Bone marrow mesenchymal stem cells induce metabolic plasticity in estrogen receptor-positive breast cancer. (PubMed, Mol Cancer Res) - "Combining syrosingopine with fulvestrant, a selective estrogen receptor degrading drug, overcame resistance of ER+ breast cancer cells in co-culture with MSCs. These data establish MSCs as a mediator of cancer cell metabolic plasticity and suggest metabolic interventions as a promising strategy to treat ER+ breast cancer and overcome resistance to standard clinical therapies. Implications: This study reveals how MSCs reprogram metabolism of ER+ breast cancer cells and point to MCT4 as potential therapeutic target to overcome resistance to anti-estrogen drugs."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

Inhibition of Oxidative Phosphorylation and Glycolysis Reduces Viability in Multiple Myeloma By Affecting mTOR-Mediated Protein Synthesis (ASH 2022) - "In conclusion, this combination strategy consisting of syrosingopine and metformin could form a new therapeutic approach to block MM progression and survival. Inge Oudaert and Arne Van der Vreken contributed equally to this work."

Hematological Malignancies • Multiple Myeloma • Oncology • ANXA5 • EIF4E • EIF4EBP1 • MCT1 • SDC1