Search Results (43)

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

Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), remains one of the most lethal gynecological malignancies due to late diagnosis and the development of chemoresistance. The tumor microenvironment (TME) plays an important role in disease progression, with chemokines influencing cell recruitment, angiogenesis, metastasis, and immune modification. This review synthesizes current evidence on key chemokine axes in ovarian cancer, highlighting their dual roles as prognostic biomarkers and therapeutic targets. The most important axes include CXCL12/CXCR4 (which drives tumor proliferation, angiogenesis and chemoresistance via epithelial–mesenchymal transition), CCL2/CCR2 (promoting immunosuppressive tumor-associated macrophages and resistance), and CCL5/CCR5 (enhancing pro-oncogenic signaling and Treg/MDSC infiltration). Pro-angiogenic ELR+CXC chemokines like CXCL8 induce vascularization and inflammation. On the contrary, effector chemokines (CXCL9/10/11/13) correlate with “hot” immune subtypes and improved survival in several studies. High expression of immunosuppressive chemokines predicts poorer prognosis and therapy resistance, while immune-attracting profiles associate with better outcomes and chemotherapy responsiveness. Therapeutically, inhibitors like plerixafor (CXCR4), PF-04136309 (CCR2), and maraviroc (CCR5) show preclinical promise, synergizing with chemotherapy, anti-VEGF, and checkpoint inhibitors. Chemokines also represent actionable molecular targets to overcome ovarian cancer’s “cold” immune phenotype. Future research should validate multi-chemokine signatures for patient stratification and advanced clinical trials toward personalized therapies. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

Background/Objectives: Patients with high-risk diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL) have suboptimal outcomes with standard therapies. Dose-adjusted R-EPOCH (R-DA-EPOCH) is often used in selected high-risk settings and may also serve as an effective chemo-mobilizing strategy for autologous stem cell transplantation (ASCT). We aimed to evaluate the impact of first-line R-DA-EPOCH on stem cell mobilization and transplantation outcomes. Methods: We retrospectively analyzed 41 consecutive adult patients with high-risk DLBCL/HGBCL treated with first-line R-DA-EPOCH between 2016 and 2021. Stem cell collection was planned after cycle 5. The primary endpoint was the rate of poor mobilizers, defined as patients who collected <2 × 10⁶ CD34⁺ cells/kg or required plerixafor (PLX) to achieve this threshold. Results: The rate of poor mobilizers was 31.7% (13/41), with 22% (9/41) of patients requiring PLX. Overall, 68% of patients achieved ≥2 × 10⁶ CD34⁺ cells/kg at first mobilization, while 88% ultimately reached the target after remobilization. Mobilization failure occurred in 12% of patients. A total of 59% of patients proceeded to ASCT. Engraftment was achieved in all transplanted patients, with no transplant-related mortality. Conclusions: First-line R-DA-EPOCH enables effective stem cell mobilization in most high-risk DLBCL and HGBCL patients, although a substantial proportion require PLX support. These findings suggest that R-DA-EPOCH is a feasible platform for early mobilization and ASCT in selected patients. 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

Alzheimer’s disease (AD) drug development faces persistent challenges from blood–brain barrier limitations and inadequate integration of medicinal chemistry considerations with computational predictions. We developed a comprehensive Central Nervous System (CNS)-focused network medicine framework integrating machine-learning-validated BBB penetration prediction (95.7% accuracy, 0.992 AUC-ROC), modality-specific tractability assessment, and transparent evidence classification to identify viable drug repurposing candidates. CNS-specific pre-filtering refined 24,474 DGIdb compounds to 8247 CNS-relevant drugs, analyzed through multi-dimensional network scoring and systematic pharmaceutical property assessment. Modality stratification generated separate rankings for small molecules (3667 candidates), peptides (73 candidates), and biologics (3 candidates), acknowledging distinct BBB penetration mechanisms. Analysis revealed 64.8% of small molecules achieving Class I (Highly Tractable) status, with 83.6% demonstrating favorable BBB penetration. Plerixafor emerged as the top-ranked small molecule (score: 1.170), while trofinetide achieved the highest peptide ranking (score: 1.387), though classified as speculative, pending AD-specific validation. Successful identification of the FDA-approved AD therapeutics memantine and donepezil among the top candidates validated the computational performance, while the predominance of mechanistic evidence classifications (86.7%) highlighted that network predictions represent hypothesis-generating tools requiring systematic experimental validation rather than definitive therapeutic recommendations. The framework bridges computational predictions with pharmaceutical development requirements, providing actionable prioritization for systematic preclinical investigation addressing AD intervention. 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

Humanized mice generated by hematopoietic stem cell (HSC) transplantation are limited by the immune system developed being allogeneic to the tumor. We have innovated a platform to reconstitute an autologous human immune system (HIS) in immunodeficient NOG-EXL mice from mobilized peripheral blood (MPB)-CD34 cells, along with PDX generated from the same patient’s tumor tissue. Patients consented under an IRB-approved protocol for tumor biopsy and HSC apheresis at Emory University. HSC collection included mobilization with G-CSF and plerixafor, immunomagnetic bead isolation with CliniMACS, and cryopreservation of CD34⁺ cells. PDX were established from biopsies or surgical specimens by passaging into immunodeficient mice. Irradiated NOG-EXL mice were engrafted with HSCs by intravenous transplantation of CD34⁺ HSC. Engraftment of human T cells, B cells, and myeloid cells in peripheral blood was assessed by serial flow cytometry of blood samples, with final assessment of immune components in spleen and bone marrow at 30 weeks. Twenty-eight PDX models were generated from 43 patients with HNSCC; 1 patient underwent apheresis. HSC engraftment in blood was observed in 100% of NOG-EXL mice at 8 weeks post-transplant, with 5–20% hCD45⁺ cells present in the periphery. B-cell development was predominant at early time points and declined over time. Human T-cell and subset development of CD4⁺ and CD8⁺ T cells were observed in blood from 15 weeks post-transplant. Strong development of the myeloid lineage (CD33⁺) was observed starting at 8 weeks and persisted throughout the study. These data demonstrate that mobilization and apheresis of HNSCC patients is technically and clinically feasible and may allow the establishment of autologous HIS-PDX mice. Full article

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics. Full article

Salvage autologous hematopoietic cell transplantation (auto-HCT) may be used to treat relapse of plasma cell myeloma occurring after previous auto-HCT. When an insufficient number of hematopoietic stem cells have been stored from the initial harvest, remobilization is necessary. Here, we aimed to analyze the efficacy and safety of different doses of cytarabine (total 800 vs. 1600 vs. 2400 mg/m²) for remobilization. Sixty-five patients, 55% male, with a median age at remobilization 63 years, were included. Remobilization was performed with cytarabine_800 in 7, cytarabine_1600 in 36, and cytarabine_2400 in 22 patients. Plerixafor rescue was used in 25% of patients receiving cytarabine_1600 and 27% of those receiving cytarabine_2400. Patients administered cytarabine_800 were not rescued with plerixafor. Remobilization was successful in 80% of patients (57% cytarabine_800; 86% cytarabine_1600; 77% cytarabine_2400; p = 0.199). The yield of collected CD34+ cells did not differ between the different cytarabine doses (p = 0.495). Patients receiving cytarabine_2400 were at the highest risk of developing severe cytopenias, requiring blood product support, or having blood-stream infections. One patient died of septic shock after cytarabine_2400. In summary, remobilization with cytarabine is feasible in most patients. All doses of cytarabine allow for successful remobilization. Cytarabine_2400 is associated with higher toxicity; therefore, lower doses (800 or 1600 mg/m²) seem to be preferable. Full article

This systematic review examines the available clinical data on CD34+ cell mobilization, collection, and engraftment in multiple myeloma patients treated with the anti-CD38 monoclonal antibodies daratumumab and isatuximab in clinical trials and in real life. Twenty-six clinical reports were published between 2019 and February 2024. Most studies documented lower circulating CD34+ cells after mobilization compared to controls, leading to higher plerixafor requirements. Although collection yields were significantly lower in approximately half of the studies, the collection target was achieved in similar proportions of daratumumab- and isatuximab-treated and nontreated patients, and access to autologous stem cell transplant (ASCT) was comparable. This could be explained by the retained efficacy of plerixafor in anti-CD38 monoclonal antibody-treated patients, while no chemotherapy-based or sparing mobilization protocol proved superior. Half of the studies reported slower hematopoietic reconstitution after ASCT in daratumumab- and isatuximab-treated patients, without an excess of infectious complications. While no direct effect on stem cells was observed in vitro, emerging evidence suggests possible dysregulation of CD34+ cell adhesion after daratumumab treatment. Overall, anti-CD38 monoclonal antibodies appear to interfere with CD34+ cell mobilization, without consistently leading to significant clinical consequences. Further research is needed to elucidate the underlying mechanisms and define optimal mobilization strategies in this patient population. Full article

Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, n = 110; D-RVd, n = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, p = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, p = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 10⁶/L, p = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 10⁶/kg BW, p = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, p = 0.0164; and 16 vs. 14 days, p = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, p = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; p = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT. Full article

Peripheral blood stem cell transplantation (PBSCT) is an important therapeutic measure for both hematologic and non-hematologic diseases. For PBSCT to be successful, sufficient CD34⁺ cells need to be mobilized and harvested. Although risk factors associated with poor mobilization in patients with hematologic diseases have been reported, studies of patients with non-hematologic diseases and those receiving plerixafor are rare. To identify factors associated with poor mobilization, data from autologous PBSC harvest (PBSCH) in 491 patients were retrospectively collected and analyzed. A multivariate analysis revealed that in patients with a hematologic disease, an age older than 60 years (odds ratio [OR] 1.655, 95% confidence interval [CI] 1.049–2.611, p = 0.008), the use of myelotoxic agents (OR 4.384, 95% CI 2.681–7.168, p < 0.001), and a low platelet count (OR 2.106, 95% CI 1.205–3.682, p = 0.009) were associated with poor mobilization. In patients with non-hematologic diseases, a history of radiation on the pelvis/spine was the sole associated factor (OR 12.200, 95% CI 1.934–76.956, p = 0.008). Among the group of patients who received plerixafor, poor mobilization was observed in 19 patients (19/134, 14.2%) and a difference in the mobilization regimen was noted among the good mobilization group. These results show that the risk factors for poor mobilization in patients with non-hematologic diseases and those receiving plerixafor differ from those in patients with hematologic diseases; as such, non-hematologic patients require special consideration to enable successful PBSCH. Full article

Mesenchymal stem cells (MSCs) have a high tropism for the hypoxic microenvironment of tumors. The combination of nanoparticles in MSCs decreases tumor growth in vitro as well as in rodent models of cancers in vivo. Covalent conjugation of nanoparticles with the surface of MSCs can significantly increase the drug load delivery in tumor sites. Nanoparticle-based anti-angiogenic systems (gold, silica and silicates, diamond, silver, and copper) prevented tumor growth in vitro. For example, glycolic acid polyconjugates enhance nanoparticle drug delivery and have been reported in human MSCs. Labeling with fluorescent particles (coumarin-6 dye) identified tumor cells using fluorescence emission in tissues; the conjugation of different types of nanoparticles in MSCs ensured success and feasibility by tracking the migration and its intratumor detection using non-invasive imaging techniques. However, the biosafety and efficacy; long-term stability of nanoparticles, and the capacity for drug release must be improved for clinical implementation. In fact, MSCs are vehicles for drug delivery with nanoparticles and also show low toxicity but inefficient accumulation in tumor sites by clearance of reticuloendothelial organs. To solve these problems, the internalization or conjugation of drug-loaded nanoparticles should be improved in MSCs. Finally, CXCR4 may prove to be a promising target for immunotherapy and cancer treatment since the delivery of siRNA to knock down this alpha chemokine receptor or CXCR4 antagonism has been shown to disrupt tumor–stromal interactions. Full article

To explore the optimal mobilization for multiple myeloma (MM) patients, we conducted a prospective trial comparing single-dose etoposide (375 mg/m² for one day) plus G-CSF versus G-CSF alone, followed by risk-adapted plerixafor. After randomization, 27 patients in the etoposide group and 29 patients in the G-CSF alone group received mobilizations. Six (22.2%) patients in the etoposide group and 15 (51.7%) patients in the G-CSF alone group received plerixafor based on a peripheral blood CD34+ cell count of < 15/mm³ (p = 0.045). The median count of CD34+ cells collected was significantly higher in the etoposide group (9.5 × 10⁶/kg vs. 7.9 × 10⁶/kg; p = 0.018), but the optimal collection rate (CD34+ cells ≥ 6 × 10⁶/kg) was not significantly different between the two groups (96.3% vs. 82.8%; p = 0.195). The rate of CD34+ cells collected of ≥ 8.0 × 10⁶/kg was significantly higher in the etoposide group (77.8% vs. 44.8%; p = 0.025). Although the rates of grade II–IV thrombocytopenia (63.0% vs. 31.0%; p = 0.031) and grade I–IV nausea (14.8% vs. 0%; p = 0.048) were significantly higher in the etoposide group, the rates of adverse events were low in both groups, with no neutropenic fever or septic shock. Thus, both single-dose etoposide plus G-CSF and G-CSF alone with risk-adapted plerixafor were effective and safe, but the former may be the better option for patients who are expected to receive two or more transplantations. Full article