Search Results (96)

Background: The C-X-C chemokine receptor type 7 (CXCR7), also known as atypical chemokine receptor 3 (ACKR3), primarily signals through β-arrestin and plays a pivotal role in tumor progression, inflammation, and neurodegenerative diseases. CXCR7 antagonists block chemokine binding and dampen β-arrestin signaling. Accordingly, identification of such antagonists is highly desirable for therapeutic development against CXCR7 driven pathologies. Methods: Through microscale thermophoresis (MST) screening of a Food and Drug Administration (FDA)-approved drug library, entacapone was identified as a CXCR7 binder. The NanoBit complementation assay was employed to evaluate the effect of entacapone on CXCR7 mediated β-arrestin 1/2 recruitment. Molecular docking was performed to predict the binding pocket and binding sites. Results: Entacapone specifically bound to CXCR7 with a Kd value of 6.04 µM. Although entacapone did not directly activate CXCR7, it selectively inhibited CXCL12 and VUF11207 induced β-arrestin 1 recruitment with no significant effect on β-arrestin 2 recruitment. Molecular docking suggested that entacapone interacted with key residues via hydrophobic contacts, including Trp100, Phe124, Gln301, and Leu305, and formed hydrogen bonds with Ser103, Asn108, and Tyr51 in the transmembrane core, collectively suggesting a possible binding mode compatible with stabilizing the receptor in an inactive conformation. Conclusions: Entacapone, a clinically well established COMT inhibitor, is reported for the first time as a novel biased antagonist of CXCR7, providing a new candidate molecule for drug repurposing. Full article

Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two therapeutic radioconjugates derived from the high-affinity CXCR4 antagonist LY2510924. Methods: The PET tracer [¹⁸F]AlF-NOTA-SC and therapeutic radioconjugates [¹⁷⁷Lu]Lu-BL02 and [¹⁶¹Tb]Tb-BL02 were synthesized and evaluated. Radiolabeling efficiency, molar activity, and in vitro binding affinity were assessed. Specificity and uptake were evaluated in CXCR4-expressing U87.CD4.CXCR4 and MM.1S cells, with cytotoxic potential being analyzed via clonogenic survival assays. In vivo biodistribution and pharmacokinetics were evaluated in MM.1S xenograft mouse models, supported by longitudinal SPECT imaging. Results: All radioconjugates were obtained with high radiochemical purity (>98%). The constructs showed nanomolar affinity for human CXCR4; in vitro assays confirmed specific uptake in CXCR4-positive cells, and both therapeutic agents demonstrated dose-dependent cytotoxicity. In vivo, all compounds displayed comparable tumor uptake with low off-target accumulation. Co-injection studies confirmed consistent pharmacokinetics across agents, while SPECT/CT imaging demonstrated gradual tumor clearance of [¹⁷⁷Lu]Lu-BL02 over seven days. Conclusions: The radiopharmaceutical trio [¹⁸F]AlF-NOTA-SC, [¹⁷⁷Lu]Lu-BL02, and [¹⁶¹Tb]Tb-BL02 demonstrates the feasibility of a CXCR4-targeted theranostic approach for imaging and treating hematologic malignancies. The observed tumor washout highlights the need for further structural optimization to enhance tumor retention and therapeutic efficacy, providing a clear direction for future development toward clinical translation. Full article

Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with 10 nM Plerixafor with or without hydroquinone (HQ), followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4/CXCR7 and integrin profiling, transwell migration assays, β-arrestin siRNA knockdown, Western blotting, subcellular fractionation, and ChIP-qPCR for β-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical Plerixafor on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration while counteracting HQ-induced suppression of melanogenic genes. In addition, it reduced cell-surface CXCR4 (consistent with β-arrestin-mediated receptor internalization) without altering CXCR7, c-KIT, or N-cadherin. β-Arrestin knockdown abolished Plerixafor-induced ERK phosphorylation and melanogenic responses, confirming β-arrestin dependence. Plerixafor promoted β-catenin nuclear translocation and direct β-catenin occupancy at MITF promoter/enhancer TCF/LEF motifs. In vivo, topical Plerixafor restored HQ-induced depigmentation, increased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a biased CXCR4 ligand in melanocytes, influencing the β-arrestin–β-catenin–MITF signaling axis to drive melanogenesis and re-pigmentation. These findings identify β-arrestin-dependent CXCR4 signaling as a tractable pharmacologic mechanism for therapeutic re-pigmentation in pigmentary disorders. Full article

Background: Visceral pain is the primary symptom of functional gastrointestinal disorders, yet its spinal molecular mechanisms remain poorly defined. Methods: Using a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced chronic inflammatory visceral pain model, the role of the spinal CXCL10/CXCR3/ERK signaling axis and the analgesic effect of docosahexaenoic acid (DHA) were investigated. Results: TNBS significantly upregulated CXCL10 and CXCR3 in spinal dorsal horn neurons and increased ERK phosphorylation. Intrathecal CXCL10-neutralizing antibody or CXCR3 antagonist NBI-74330 reduced visceral hypersensitivity and suppressed spinal ERK activation in TNBS mice. Exogenous CXCL10 induced CXCR3-dependent hyperalgesia and ERK phosphorylation in the spinal cord. Intrathecal DHA attenuated TNBS-induced visceral pain, downregulated spinal CXCL10/CXCR3 expression, and inhibited ERK signaling. In Neuro-2a cells, DHA also blocked LPS-induced activation of the same pathway. Conclusions: This study suggests that the analgesic effect of DHA may involve the inhibition of the spinal CXCL10/CXCR3/ERK signaling pathway. Full article

Lung cancer remains a major public health challenge due to high incidence and mortality. The chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1) constitute a critical axis in tumor biology, influencing tumor cell proliferation, invasion, angiogenesis, and immune evasion. Aberrant CXCR4 expression is frequently observed in lung cancer and is closely associated with adverse prognosis, enhanced metastatic potential, and therapeutic resistance. Mechanistically, CXCR4 activates signaling pathways including PI3K/AKT, MAPK/ERK, JAK/STAT, and FAK/Src, promoting epithelial–mesenchymal transition, stemness, and survival. The CXCL12/CXCR4 axis also orchestrates interactions with the tumor microenvironment, facilitating chemotaxis toward CXCL12-rich niches (e.g., bone marrow and brain) and modulating anti-tumor immunity via regulatory cells. Regulation of CXCR4 occurs at transcriptional, epigenetic, and post-transcriptional levels, with modulation by hypoxia, inflammatory signals, microRNAs, and post-translational modifications. Clinically, high CXCR4 expression correlates with metastasis, poor prognosis, and reduced response to certain therapies, underscoring its potential as a prognostic biomarker and therapeutic target. Therapeutic strategies targeting CXCR4 include small-molecule antagonists (e.g., AMD3100/plerixafor; balixafortide), anti-CXCR4 antibodies, and CXCL12 decoys, as well as imaging probes for patient selection and response monitoring (e.g., 68Ga-pentixafor PET). Preclinical and early clinical studies suggest that CXCR4 blockade can impair tumor growth, limit metastatic spread, and enhance chemotherapy and immunotherapy efficacy, although hematopoietic side effects and infection risk necessitate careful therapeutic design. This review synthesizes the molecular features, regulatory networks, and translational potential of CXCR4 in lung cancer and discusses future directions for precision therapy and biomarker-guided intervention. Full article

Chronic lymphocytic leukemia (CLL) is an indolent malignancy with modest proliferation in the lymph nodes and accumulation of quiescent B cells in the peripheral blood. Targeted agents, including BTK inhibitors such as ibrutinib and the BCL2 antagonist venetoclax, have transformed therapy by disrupting proliferation, survival, and lymph node retention of CLL cells, yet CLL remains incurable. Recent studies reveal that CLL cells exist along a spectrum of proliferating, activated, and quiescent states, with dynamic transitions that shape intraclonal behavior. Whilst proliferation occurs mainly in lymph nodes, most emigrant cells in the peripheral blood become quiescent, with only a minority remaining activated. Quiescent, activated, and proliferating fractions display distinct phenotypes and CXCR4 and CD5 levels can be used to distinguish these states in the CLL life cycle. While proliferating and activated cells are more susceptible to BTK inhibition, quiescent subsets show greater sensitivity to BCL2 blockade. These functional differences, together with emerging evidence that phenotypic markers may correlate with residual disease activity, point to potential translational significance. Understanding how CLL cells switch between proliferative, activated and quiescent states will be important to uncover novel vulnerabilities and inform rational treatment strategies. Full article

Sepsis remains a major cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions characterized by high mortality and limited therapeutic options. Among the diverse inflammatory pathways implicated in their pathogenesis, the CXCL12/CXCR4 chemokine axis has gained increasing attention for its dual capacity to drive acute inflammation while also supporting tissue repair. Although numerous studies have investigated this signaling pathway, an integrated framework that reconciles its context-dependent functions, upstream regulatory mechanisms, and translational relevance has been lacking. In this review, we synthesize current evidence on the multifaceted roles of the CXCL12/CXCR4 axis in sepsis-induced ALI, highlighting its cell-type-specific effects in neutrophils, macrophages, alveolar epithelial cells, and endothelial cells through downstream pathways such as NF-κB, MAPK, and PI3K/Akt. We further evaluate emerging therapeutic approaches, including small-molecule antagonists (e.g., AMD3100), natural products, and epigenetic modulators. Newly added sections summarize the upstream regulation of CXCL12 by hypoxia, cytokines, and epigenetic factors, discuss the regulatory influence of the alternative receptor CXCR7/ACKR3, and differentiate preclinical insights from human clinical observations. Finally, we outline key obstacles to clinical translation and propose future directions to develop precision medicine strategies that more effectively target this axis. Collectively, our analysis suggests that although the CXCL12/CXCR4 pathway represents a promising target for ALI/ARDS therapy, its context-dependent and cell-specific actions demand carefully tailored modulation rather than uniform inhibition. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) therapies are limited by poor response, rapid resistance, and recurrence of aggressive disease. Sorafenib, a multi-tyrosine kinase inhibitor, can trigger β-catenin stabilization and activation, contributing to resistance. Overexpression of the chemokine receptor CXCR6 and its ligand CXCL16 and hyperactivation are implicated in HCC progression and β-catenin stabilization. We hypothesized that SBI-457, a small-molecule CXCR6 antagonist we developed, could disrupt CXCR6/β-catenin crosstalk and enhance sorafenib sensitivity. Methods: We tested SBI-457 alone and in combination with sorafenib in SK-Hep-1 xenograft models and a panel of human HCC cell lines. Tumor burden, β-catenin activation, and CXCR6 expression were assessed by tumor volume measurements, immunohistochemistry, Western blotting, and immunofluorescence. Soluble CXCL16 levels were quantified by ELISA, and cell death responses were evaluated using MTT assays. Results: In vivo, SBI-457 combined with sorafenib reduced normalized tumor volume by 55% compared to vehicle controls, modestly exceeding monotherapy effects, and attenuated sorafenib-induced β-catenin upregulation. In vitro, SBI-457 blocked nuclear accumulation of β-catenin and reversed sorafenib-induced increases in β-catenin levels. Enhanced cell death was observed in specific “responder” HCC cell lines (Hep-3B, SNU-398, JHH-5), which correlated with high intracellular β-catenin, secretion of soluble CXCL16, and expression of a high molecular weight form of CXCR6. In contrast, “non-responder” cell lines with conventional CXCR6 expression and low CXCL16 secretion showed no enhanced cell death response. Conclusions: CXCR6 antagonism with SBI-457 can modulate β-catenin activation and may help overcome sorafenib resistance in selected HCC models. These findings support further development of CXCR6 antagonists as single agents or combination therapies to improve treatment outcomes in HCC. Full article

Metastatic breast carcinoma (BC) cells are prone to spreading in the bone microenvironment, leading to a vicious cycle between local osteoclast-mediated osteolysis and tumor progression. Therefore, the targeted pharmacological down-modulation of BC cell proliferation as well as osteoclast differentiation and hyperactivity might represent a promising treatment option. We developed a multifunctional peptide nanocarrier combining bioactive EPI-X4 peptides and the Rho-inhibiting C3bot enzyme from Clostridium botulinum. C3bot is preferentially internalized into the cytosol of monocytic cells, including osteoclasts, where it inhibits Rho-mediated signal transduction. However, Rho-mediated cellular processes like migration and cell division can also be inhibited in non-monocytic cells if C3bot is delivered into their cytosol by a nanocarrier. To accomplish this, we designed a supramolecular transporter where one molecule of biotinylated C3bot and three biotinylated entities of the human EPI-X4 peptide-derived CXCR4 antagonist JM173 are assembled on avidin as a central platform. This modular transport system (JM173)₃-Avi-C3 down-modulated osteoclast formation and hyperactivity and delivered the therapeutic cargo C3bot successfully into the cytosol of breast cancer cells, where it inhibited Rho. Full article

Background: This study addresses an important vulnerability in the treatment of high-risk neuroblastoma (NB). NB is characterized by high rates of metastasis, drug resistance, relapse, and treatment-related toxicities. Current treatments, which include intensive chemotherapy, surgical removal of tumors, and stem cell transplants, have less than 50 percent survival rates among high-risk NB patients, demonstrating the need for novel targeted treatment approaches. CXC chemokine receptor 2 (CXCR2), a G-protein-coupled receptor, has been implicated in promoting cancer cell proliferation, invasion, metastasis, angiogenesis, chemoresistance, and maintaining cancer stem cells. Methods: We analyzed transcriptomic data from 1464 primary NB patient samples to evaluate the prognostic significance of CXCR2 expression. Pharmacological inhibition of CXCR2 using SB225002, a selective small-molecule antagonist, was evaluated to determine its effects on cell growth, colony formation, apoptosis, and cell cycle progression in different NB cell lines. Three-dimensional (3D) spheroid models were used to examine tumor growth under physiologically relevant conditions. Mechanistic studies included gene expression analyses and immunoblot validation of key signaling regulators. Results: High CXCR2 expression was found to be inversely correlated with overall survival in patient datasets, suggesting a role in NB pathogenesis. Treatment with SB225002 significantly inhibited NB proliferation and colony formation while inducing apoptosis and cell cycle arrest in a dose-dependent manner. In 3D spheroid models, SB225002 significantly impaired spheroid formation and growth, confirming its potent anti-tumor efficacy. Mechanistically, CXCR2 blockade inhibited the expression of key pathway targets, including GLIPR1, BACH2, JUN, CHEK1, AKT1, and CXCR2 itself. Immunoblot analysis confirmed significant inhibition of CXCR2 and GLIPR1 protein levels in response to SB225002 treatment. Conclusions: Taken together, our findings demonstrate that pharmacological inhibition of CXCR2 using SB225002 effectively inhibits NB tumor cell growth and tumorigenicity by modulating oncogenic signaling networks. This study provides strong evidence for elucidating CXCR2-targeted therapies as an attractive treatment option for NB. These findings support the development of CXCR2-targeted therapies for high-risk NB. Full article

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant forms. TNBC is an aggressive and therapeutically resistant subtype of breast cancer, marked by the absence of estrogen, progesterone, and HER2 receptors. The lack of defined molecular targets significantly limits treatment options and contributes to high recurrence rates. Among the key pathways involved in TNBC progression and resistance, the CXCR4/CXCL12 chemokine axis has emerged as a critical player. CXCR4, a G-protein-coupled receptor, binds specifically to its ligand CXCL12, promoting tumour cell proliferation, metastasis, immune evasion, and stromal remodelling. Its overexpression is frequently associated with poor prognosis, disease progression, and resistance to conventional therapies in TNBC. This review explores how the chemokine receptor type 4 (CXCR4/CXCL12) axis facilitates drug resistance through mechanisms such as epithelial–mesenchymal transition (EMT), cancer stemness, and microenvironmental interactions. Notably, CXCR4 antagonists like plerixafor, balixafortide, and POL5551 have shown encouraging preclinical and clinical results, particularly when combined with chemotherapy or immunotherapy. Additionally, innovative strategies, including radiopharmaceuticals, peptide inhibitors, and nanotechnology-based delivery platforms, offer expanded therapeutic avenues. Despite persistent challenges such as tumour heterogeneity and potential toxicity, growing clinical evidence supports the translational relevance of this axis. This manuscript provides an in-depth analysis of CXCR4/CXCL12-mediated drug resistance in TNBC and evaluates current and emerging therapeutic interventions. Full article

Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) are clonal hematologic malignancies characterized not only by driver mutations such as JAK2V617F, CALR, and MPL but also by a profoundly dysregulated immune microenvironment. Chronic inflammation and immune remodeling sustain malignant hematopoiesis and contribute to disease progression from essential thrombocythemia (ET) and polycythemia vera (PV) to overt myelofibrosis (MF). Pro-inflammatory cytokines and chemokines—including IL-2, IFN-α, IL-23, and TNF-α—drive abnormal T cell polarization, favoring a pathogenic Th17 phenotype. Lymphocyte subset analysis reveals a predominance of exhausted PD-1⁺ T cells, reflecting impaired immune surveillance. Concurrently, alterations in neutrophil apoptosis lead to persistent inflammation and stromal activation. GRO-α (CXCL1) is elevated in ET but reduced in MF, suggesting a subtype-specific role in disease biology. Fibrosis-promoting factors such as TGF-β and IL-13 mediate bone marrow remodeling and megakaryocyte expansion, while VEGF and other angiogenic factors enhance vascular niche alterations, particularly in PV. These immunopathologic features underscore novel therapeutic vulnerabilities. In addition to JAK inhibition, targeted strategies such as CXCR1/2 antagonists, anti-TGF-β agents, and immune checkpoint inhibitors (PD-1/PD-L1 blockade) may offer disease-modifying potential. Understanding the interplay between cytokine signaling and immune cell dysfunction is crucial for developing precision immunotherapies in MPNs. Full article

This study aimed to investigate the molecular binding mechanisms of bromocriptine toward histamine-associated targets, exploring both antagonist-like and other potential interaction modes that may support therapeutic repurposing. Network pharmacology was applied to identify histamine-related pathways and prioritize potential protein targets. CXCR4, GHSR, and OXTR were selected based on combined docking scores and pharmacophore modeling evidence. Molecular dynamics (MD) simulations over 100 ns assessed structural stability, flexibility, compactness, and solvent exposure. Binding site contact analysis and MM/PBSA free binding energy calculations were conducted to characterize binding energetics and interaction persistence. Bromocriptine exhibited stable binding to all three receptors, engaging key residues implicated in receptor modulation (e.g., Asp187 in CXCR4, Asp99 in GHSR, Arg232 in OXTR). The MM/PBSA ΔG_binding values of bromocriptine were −22.67 ± 3.70 kcal/mol (CXCR4 complex), −22.11 ± 3.55 kcal/mol (GHSR complex), and −21.43 ± 2.41 kcal/mol (OXTR complex), stronger than standard agonists and comparable to antagonists. Contact profiles revealed shared and unique binding patterns across targets, reflecting their potential for diverse modulatory effects. Bromocriptine demonstrates high-affinity binding to multiple histamine-associated GPCR targets, potentially exerting both inhibitory and modulatory actions. These findings provide a molecular basis for further experimental validation and therapeutic exploration in histamine-related conditions. Full article

Bone is the most frequent site of distant metastasis in advanced prostate cancer (PCa), contributing substantially to patient morbidity and mortality. Hypoxia, a defining feature of the solid tumour microenvironment, plays a pivotal role in driving bone-tropic progression by promoting epithelial-to-mesenchymal transition (EMT), cancer stemness, extracellular matrix (ECM) remodelling, and activation of key signalling pathways such as Wingless/Integrated (Wnt) Wnt/β-catenin and PI3K/Akt. Hypoxia also enhances the secretion of extracellular vesicles (EVs), enriched with pro-metastatic cargos, and upregulates bone-homing molecules including CXCR4, integrins, and PIM kinases, fostering pre-metastatic niche formation and skeletal colonisation. In this review, we analysed current evidence on how hypoxia orchestrates PCa dissemination to bone, focusing on the molecular crosstalk between HIF signalling, Wnt activation, EV-mediated communication, and cellular plasticity. We further explore therapeutic strategies targeting hypoxia-related pathways, such as HIF inhibitors, hypoxia-activated prodrugs, and Wnt antagonists, with an emphasis on overcoming therapy resistance in castration-resistant PCa (CRPC). By examining the mechanistic underpinnings of hypoxia-driven bone metastasis, we highlight promising translational avenues for improving patient outcomes in advanced PCa. Full article

CXCL1 (Gro-α, MGSA) is a chemokine functionally similar to CXCL8/IL-8, as both activate the same receptor, CXCR2. CXCL1 levels are frequently elevated in tumors compared to healthy tissue, where they play a key role in promoting cancer cell migration, angiogenesis, and neutrophil recruitment. While the involvement of CXCL1 in tumor progression is well established, its relevance to cancer therapy remains underexplored. This review examines the therapeutic potential of targeting CXCL1 and its receptor, CXCR2, in cancer treatment. It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. Particular attention is given to the role of CXCL1 in treatment resistance, including resistance to chemotherapy, radiotherapy, and anti-angiogenic therapy. Cancer therapies often upregulate CXCL1 expression, which in turn drives treatment resistance. Additionally, this review explores the contribution of CXCL1 to therapy-induced side effects, such as chemotherapy-induced metastasis, neuropathy, nephrotoxicity, diarrhea, and cardiotoxicity. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions. Full article