Background/Objectives: During prostate cancer progression, downregulation or loss of prostate-specific membrane antigen (PSMA) expression, together with interlesional heterogeneity, may limit the efficacy of PSMA-targeted radioligand therapy. Fibroblast activation protein (FAP), expressed mainly by activated cancer-associated fibroblasts in the tumor microenvironment, represents a potential complementary target. We developed the PSMA/FAP bispecific radioligand with a biphenyl scaffold and evaluated its feasibility and therapeutic potential. Methods: The radiochemical purity and in vitro stability were evaluated by Radio-HPLC. Cellular uptake was evaluated in 22Rv1 (PSMA+), U87MG (FAP+), and PC-3 (PSMA−/FAP−) cells. SPECT/CT imaging and biodistribution studies were performed using mice bearing separate 22Rv1 (PSMA+) and U87MG (FAP+) xenografts. Therapeutic efficacy was assessed after a single administration of 30 or 60 MBq [177Lu]Lu-PSFA-1, together with an acute toxicity evaluation. Results: [177Lu]Lu-PSFA-1 showed PSMA- and FAP-associated uptake. SPECT/CT imaging and biodistribution studies showed persistent uptake in both tumor types, with higher uptake in U87MG tumors and increasing tumor-to-background ratios over time. A single administration of 30 or 60 MBq delayed tumor growth and prolonged survival, with more durable tumor control at 60 MBq. No evident acute toxicity was observed. Conclusions: [177Lu]Lu-PSFA-1 specifically targeted both PSMA- and FAP-positive tumors, with sustained tumor retention and antitumor activity. These findings support further evaluation of [177Lu]Lu-PSFA-1 as a PSMA/FAP bispecific radioligand, although its potential benefit in heterogeneous prostate cancer requires further validation.
Background/Objective: Plant-derived vesicular preparations are a heterogeneous class of products being studied for their potential applications in cancer, inflammatory bowel disease, and metabolic disorders. This review focuses primarily on oncology as a case study while also exploring findings in other non-oncological fields, evaluating the source of the preparations, the causal relationships of their constituents, and the evidence for their translational applications. Methods: On 29 September 2026, we updated the authors’ compiled reference list through a PubMed search of the literature and verified the preparation type, dosage, and mechanism of action in the cited original studies. Results: The existing evidence still primarily stems from preclinical studies. Three tissue-destructive formulations validated by intervention studies provide more informative oncological mechanisms than studies involving only the ingestion process; however, none met the criteria for comprehensive evidence regarding secreted plant-derived vesicles (PDEVs). Across different models, ginger formulations modulate intestinal inflammation and insulin response, while lemon and orange formulations are associated with hepatic redox or metabolic outcomes. These products and their endpoints cannot be consolidated into a single mechanism of action or efficacy assessment. Conclusions: Across various indications, product identity, active dose, target cell exposure, causal intervention, comparators, and the safety of repeated dosing remain essential before clinical claims can be made. Unless new therapeutic uses can be demonstrated, reformulation of existing drugs constitutes merely a formulation improvement.
Background/Objectives: Platinum resistance limits the efficacy of ovarian cancer treatment and arises through multiple mechanisms, including enhanced DNA repair, activation of stress responses, and increased survival signaling. Nelfinavir (NFV), an HIV protease inhibitor with reported anti-tumor activity, is a candidate for drug repurposing, but its interaction with cisplatin (CDDP) in ovarian cancer has not been established. Here, we investigated whether NFV enhances CDDP cytotoxicity in platinum (Pt)-resistant ovarian cancer cells and characterized the associated cell death response. Methods: Drug interaction was assessed using cell vitality and viability assays and Loewe additivity modeling together with Bliss and ZIP analyses. Cell death was characterized by Annexin V/7-AAD staining, mitochondrial membrane potential analysis, lactate dehydrogenase (LDH) release, immunoblotting, pharmacological caspase inhibition, and bulk mRNA sequencing with differential expression and gene set enrichment analyses. Results: NFV synergistically enhanced CDDP cytotoxicity across three Pt-resistant ovarian cancer cell lines, reducing CDDP IC50 values by 4.2–5.8-fold and producing mean Loewe synergy scores of approximately 25–30. Combination treatment increased LDH release and was accompanied by caspase-8, caspase-3, PARP, and the pore-forming death effector gasdermin E (GSDME) cleavage. Caspase inhibition attenuated viability loss and GSDME processing. Transcriptomic analysis identified enrichment of stress- and death-associated programs, including the unfolded protein response (UPR), apoptosis, reactive oxygen species (ROS)-associated signaling, and TNF/NF-κB signaling. Conclusions: Together, these findings demonstrate a reproducible synergistic interaction between CDDP and NFV in Pt-resistant ovarian cancer cells and characterize an associated lytic cell death phenotype involving apoptotic signaling and accompanied by GSDME processing. These findings support further investigation of NFV as a repurposed combination partner to enhance CDDP cytotoxicity in Pt-resistant ovarian cancer.
Background/Objectives: Acyclovir, valacyclovir, and famciclovir are widely used antiviral agents, but comparative data on neuropsychiatric adverse event reporting are limited. This study’s aim was to compare neuropsychiatric adverse event reporting among acyclovir, valacyclovir, and famciclovir and to evaluate the influence of demographic and temporal factors. Methods: A retrospective pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System (FAERS, Q4 2003–Q3 2025). Unique reports in which acyclovir, valacyclovir, or famciclovir was the primary suspect drug were analyzed. Disproportionality was assessed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC). Between-drug differences in the proportion of neuropsychiatric reports were examined using multivariable logistic regression adjusted for age, sex, region (with Japan as a separate category), and reporting year, together with overlap and inverse probability weighting and sensitivity analyses. A narrow clinical phenotype (encephalopathy/neurotoxicity, altered consciousness/delirium, hallucination/psychosis, and seizure) was the primary outcome, and a broad System Organ Class (SOC)-based definition was a secondary outcome. Results: Of 16,071 unique primary-suspect reports (acyclovir, 6641; valacyclovir, 8980; famciclovir, 450), 4942 (30.8%) contained at least one nervous system or psychiatric Preferred Term (broad definition), and 2471 (15.4%) contained the narrow phenotype. All three drugs showed strong disproportionality signals for encephalopathy-related terms (e.g., toxic encephalopathy ROR 71.63 for acyclovir and 123.39 for valacyclovir; neurotoxicity ROR 55.74 and 48.57, respectively). For the primary narrow phenotype, reporting did not differ between valacyclovir and acyclovir (aOR 1.06, 95% CI 0.96–1.17) and was not higher for famciclovir (aOR 0.72, 95% CI 0.54–0.96; adjusted p = 0.055). Only with the secondary broad definition was the adjusted proportion of neuropsychiatric reports higher for valacyclovir (aOR 1.15, 95% CI 1.07–1.24) and famciclovir (aOR 1.41, 95% CI 1.14–1.75) than for acyclovir. The valacyclovir difference was confined to reports from Japan (aOR 1.88, 95% CI 1.52–2.33) and was absent elsewhere (aOR 1.06, 95% CI 0.98–1.15; interaction p < 0.001), whereas the famciclovir excess reflected non-specific terms such as dizziness and headache. Older age was independently associated with neuropsychiatric reporting (narrow phenotype: aOR 2.52, 95% CI 2.24–2.82). Conclusions: Acyclovir, valacyclovir, and famciclovir share a consistent, encephalopathy-dominated neuropsychiatric reporting signal in FAERS. Apparent between-drug differences depended on the case definition and on reports from Japan and should not be interpreted as differences in neurotoxic risk. Clinical vigilance for encephalopathy is warranted with all three agents, particularly in older patients, while recognizing that FAERS data cannot establish causality or absolute risk.
Background/Objective: Casein kinase 1δ (CK1δ) plays a central role in regulating circadian rhythms, DNA repair, apoptosis, and cell proliferation, and its dysregulation is associated with both cancer and neurodegenerative diseases, making CK1δ an attractive therapeutic target. This study aimed to develop novel CK1δ inhibitors with favourable drug-like properties through the synthesis and biological evaluation of benzimidazol-2-acetamide derivatives. Methods: A novel series of benzimidazol-2-acetamide derivatives was synthesized, incorporating different substituents on the benzimidazole core (5-chloro, 5,6-dichloro, 5-nitro, and 5-cyano) and various saturated cyclic amines on the acetamide moiety. Compounds were evaluated for CK1δ inhibitory activity, while molecular docking and molecular dynamics simulations were performed to investigate their binding mode. In silico ADME predictions assessed pharmacokinetic properties, and cytotoxicity was evaluated in SH-SY5Y neuroblastoma cells. Results: The 5,6-dichloro derivatives 20 and 24, bearing piperidin-4-ylmethanamine and morpholine moieties, respectively, displayed the highest CK1δ inhibitory activity (IC50 = 0.172 and 0.223 μM). The 5-cyano analogue 22 also exhibited a good potency (IC50 = 0.224 μM). Computational studies confirmed an ATP-competitive binding mode and highlighted the dynamic behaviour of the solvent-exposed substituents within the CK1δ binding site. Predicted pharmacokinetic properties suggested favourable oral absorption and blood–brain barrier penetration. Compounds 20, 22, and 24 showed no cytotoxicity in SH-SY5Y cells at concentrations up to 10 μM. Conclusions: The new benzimidazol-2-acetamide derivatives exhibited good inhibitor activity against CK1δ, favourable predicted ADME properties, and low cellular toxicity. The combined experimental and computational findings provide valuable insights for the further optimization of this scaffold toward the development of therapeutics for CK1δ-related diseases.
