Search Results (1,216)

Dimethyl fumarate (DMF) is a clinically approved fumarate ester with pleiotropic effects and a promising candidate for drug repurposing in cancer. Here, we investigated whether low-dose DMF could modulate docetaxel (DCT) responses in prostate cancer cells. PC-3, LNCaP, and RWPE-1 cells were exposed to DMF and DCT individually or in combination, and cell viability, drug interaction profiles, apoptosis, oxidative stress, mitochondrial mass, glutathione status, glucose consumption, lactate production, LDHA/SOD2 expression, and oxygen consumption were evaluated. Low-dose DMF and DCT were well-tolerated in RWPE-1 normal prostate cells. In prostate cancer cells, the DMF–DCT combination was cytotoxic and strongly dose- and ratio-dependent, with the most favorable responses at higher exposures and under balanced or DCT-enriched regimens. DMF-DCT-treated LNCaP cells showed reduced viability, decreased lactate production, increased glucose consumption, mitochondrial dysfunction, oxidative stress, downregulation of LDHA and SOD2, and caspase-associated apoptosis. In contrast, PC-3 cells showed greater combinatorial susceptibility, a docetaxel dose-sparing effect, and a low glycolytic profile, with concomitant cytotoxicity and mitochondrial dysfunction. These findings identify DMF as a context-dependent metabolic modulator of docetaxel response, supporting further evaluation of DMF–DCT combinations as a potential therapeutic strategy in prostate cancer. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, and the efficacy of conventional chemotherapy is frequently limited by systemic toxicity, chemoresistance, and tumor recurrence. Natural products derived from marine algae and plants have attracted increasing interest as multitarget adjuvant agents capable of modulating apoptosis, oxidative stress, and tumor-associated signaling pathways. In the present study, we evaluated the anticancer activity of commercially available formulations enriched in fucoxanthin, fucoidan, tocotrienols, astaxanthin, and apple polyphenols, either alone or in combination with doxorubicin (DOX), using two-dimensional and three-dimensional colorectal cancer models. Initial IC₅₀ screening in ovarian (OVCAR3), prostate (PC3), colorectal (Caco2 and HT-29), and non-tumorigenic colon epithelial cells demonstrated that formulations 2.1 and 10.0 exhibited the most relevant cytotoxic activity, particularly in colorectal cancer cells. Combined treatments with DOX significantly reduced cell viability compared to individual treatments, particularly in Caco2 cells, where viability decreased to approximately 10% under combined exposure conditions. Mechanistically, combined treatments enhanced caspase-3/7 activation in both Caco2 and HT-29 cells, indicating apoptosis-associated effects. These findings were further supported in three-dimensional spheroid models, where supplement combinations impaired spheroid expansion, induced apoptotic AO/EB staining patterns, and reduced HT-29 spheroid growth by approximately 30–35%, reaching inhibitory effects comparable to DOX alone. Collectively, these results suggest that plant- and algae-derived formulations enriched in antioxidant bioactives may enhance chemotherapy-associated antitumor responses through apoptosis-related mechanisms and modulation of tumor-like growth behavior. The present findings support the further exploration of natural-product-based adjuvant strategies in colorectal cancer therapy using more clinically representative chemotherapeutic schemes and in vivo models. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Introduction: Prostate cancer (PC) is a highly prevalent malignant tumour associated with significant morbidity and mortality. While physical activity has been linked to a lower risk of PC and exercise has been shown to reduce mortality, the evidence for the association between physical activity and mortality is limited. Objective: This study aimed to assess the association between physical activity and mortality risk in men with or at risk of PC. Methods: A systematic search was conducted in Medline, Scopus and Web of Science from inception until April 2026. Observational studies analysing physical activity and all-cause and PC-specific mortality were included. The data were synthesised and interpreted using a synthesis without meta-analysis (SWiM) approach. The quality of the studies was assessed using the NHLBI tool. The certainty of the evidence was assessed using the GRADE framework. Results: Fifteen observational studies were included. The hazard ratio (HR) was the predominant effect measure. Physical activity was associated with a reduction in all-cause mortality (HRs: 0.40–0.88; highest versus lowest categories), and a dose–response gradient was observed within two cohorts. Associations with PC-specific mortality were less consistent, with significant inverse findings concentrated in post-diagnosis assessments. The quality of the studies was generally poor, and the certainty of the evidence was very low for both outcomes. Conclusions: Physical activity was associated with lower all-cause mortality risk in men with or at risk of PC, and the most consistent inverse estimates were observed in post-diagnostic assessments. These findings are observational and should not be interpreted as a clinical recommendation. A dose–response pattern was noted within individual studies, although the certainty of evidence was very low for this outcome. Additionally, evidence for PC-specific mortality was inconsistent and of very low certainty. Prospective studies with standardised, objective measures of physical activity are required. Full article

Redox homeostasis is the balance between oxidative processes and antioxidant defenses and is fundamental to cellular integrity. This review critically synthesizes current evidence on the phytochemical composition, redox-modulating mechanisms, and therapeutic bioactivities of Fagonia cretica L. (F. cretica), with the aim of evaluating its translational potential as a natural antioxidant and anticancer agent. F. cretica has emerged as a phytochemically rich candidate containing highly bioactive secondary metabolite for redox-targeted therapeutic applications. Its diverse secondary metabolite profile, including alkaloids, flavonoids, tannins, saponins, terpenoids, glycosides, and phenolic compounds, confers broad biological activity. Bioactive constituents, particularly kaempferol, catechin, quercetin, and arbutin, directly neutralize reactive oxygen species (ROS) and modulate inflammatory pathways through inhibition of COX-1, COX-2, and nitric oxide production. These compounds influence important major ROS-sensitive redox signaling pathways: activation of the Keap1/Nrf2/ARE axis to upregulate cytoprotective genes such as HO-1, NQO1, and GCL, suppression of the NF-κB pathway to attenuate pro-inflammatory cytokine transcription, including TNF-α, IL-1β, and IL-6, and interference with the MAPK-PI3K/Akt cascade to disrupt aberrant cancer cell survival and proliferation. Bioactive compound-rich extracts of F. cretica exhibit anticancer activity in MCF-7 breast cancer cells by inducing DNA damage, cell cycle arrest, and apoptotic signaling through the FOXO3a/p53 pathways. Similar effects have been reported in colorectal (HCT-116) and prostate (PC-3) cancer cells through DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation, oxidative stress induction, and ER-β activation. Moreover, these extracts demonstrate cytotoxic effects in HepG2 and Caco-2 intestinal cancer cells, often associated with topoisomerase inhibition and caspase activation. Despite encouraging preclinical evidence, systematic studies encompassing pharmacokinetic profiling, toxicological characterization, and human clinical trials remain essential to translate these findings into safe, evidence-based therapeutic applications. Full article

Prostate cancer (PCa) is one of the most common causes of cancer-related mortality in men globally. Although current therapies can control early-stage disease, advanced PCa remains difficult to treat because of therapeutic resistance and adverse side effects, highlighting the need for new treatment strategies. Syzygium nervosum (SN), a medicinal plant rich in bioactive compounds such as gallic acid and ellagic acid, has demonstrated anticancer properties in several malignancies; however, its effects on PCa remain unclear. This study investigated the anticancer potential of SN using integrated computational and in vitro approaches. DU145 and PC-3 prostate cancer cells were treated with SN extract at concentrations of 25–400 µg/mL for 24 and 48 h. Cell viability, colony formation, and cell-cycle progression were evaluated to determine antiproliferative activity. In parallel, computational analyses were performed to predict molecular targets of SN-derived compounds. Our results displayed that SN extract reduced cell viability, suppressed clonogenic growth, and disrupted cell-cycle progression in both cell lines. Computational findings suggested that gallic and ellagic acids may interact with key regulatory proteins related to cell proliferation and survival, including AKT and CDK2. Overall, SN demonstrates promising anticancer activity and may represent a potential therapeutic source for prostate cancer treatment. Full article

Background: Cancer-related cachexia is primarily characterized by systemic inflammation and progressive muscle wasting, which is why a high-protein diet (from 1.2 to 1.5 g/kg/day) is commonly recommended. However, concerns remain that an excessive supply of amino acids could promote tumor growth due to the metabolic flexibility of cancer cells, thereby favoring proliferation and survival. Systematic evidence addressing these concerns under controlled conditions for various types of cancer cells remains limited and inconclusive. Methods: We investigated the short-term effects of all 20 amino acids at both moderate (2×) and high (10×) concentrations to evaluate three key oncological endpoints in four human cancer cell lines: MDA-MB-231 (breast), HT29 (colorectal), PC3 (prostate), and PANC-1 (pancreatic). Cell proliferation was assessed by BrdU incorporation, metabolic activity by WST-1 assay, and apoptosis signaling by caspase-3/7 activity measurement. Results: Amino acid supplementation was not associated with a significant change in proliferation at either concentration across all four cell lines studied. Metabolic activity showed only minor variations throughout, with PC3 cells exhibiting slightly greater variability, although this did not reach statistical significance. Caspase-3/7 activity remained largely unchanged under all conditions; however, high-concentration lysine induced an approximately 2.5-fold increase in PANC1 cells, which was not statistically significant. Conclusions: These findings suggest that short-term exposure to individual amino acids, even at supraphysiological conditions, does not acutely enhance proliferative activity in the cancer cell lines studied, supporting the rationale for adequate protein and amino acid intake in patients with cancer cachexia. Full article

Background/Objectives: Genetic testing (GT) is essential for precision therapy in prostate cancer (PC). Implementation in routine outpatient cancer care remains heterogeneous. We assessed real-world data on GT practices among German Outpatient Urologists (GOUs) to identify strategies for improvement. Methods: A nationwide, multi-center survey was conducted among GOUs in Germany (02–06/2025), assessing demographics, qualifications, and GT behavior. Cochran-Armitage test for trend and Fisher’s exact test were used to assess associations; odds ratios with 95% confidence intervals were estimated using binary logistic regression. Results: In total, 117 GOUs participated, all practiced in outpatient settings. GT differed by disease stage: in localized prostate cancer, 6.0% reported ordering somatic testing (SoT) and 8.5% germline testing (GeT), compared to 67.5% and 42.7%, respectively, in metastatic disease. Overall, 29.1% reported not ordering GT of any kind. Ordering SoT for metastatic disease was significantly lower among senior physicians compared to early- and mid-career physicians (43% vs. 78% and 74%; OR 0.46 per career stage, 95% CI 0.27–0.79, p = 0.004). GeT did not differ significantly by experience (OR 0.90 per career stage, 95% CI 0.56–1.46, p = 0.67). Neither gender (OR 0.74, 95% CI 0.31–1.74), nor having a qualification in urological cancer-specific genetic counseling (26.5% of respondents; OR 0.81, 95% CI 0.33–1.98) was significantly associated with testing. BRCA1 and BRCA2 were recognized by 96.6% of respondents. Knowledge of other PC-associated genes was much lower. Conclusions: Despite guideline recommendations, GT, particularly GeT, remains underutilized in PC care in Germany. Senior physicians tested significantly less, and gene knowledge beyond BRCA1/2 was limited. Full article

Dietary factors, including the consumption of isoflavones-rich foods of plant origin, may contribute to the reduced incidence of prostate cancer. Isoflavones, natural phytoestrogens often found in legumes, can modulate estrogen and androgen receptor signaling. This study aimed to evaluate the biological potential of isoflavone-rich extracts obtained from twelve species from the Fabaceae family, targeting prostate cancer cell viability, proliferation, inflammatory markers, prostate-specific antigen secretion, and 5α-reductase activity. The tested extracts showed moderate cytotoxic activity against prostate cancer cell lines, apart from highly susceptible PC3 cells, and only weak toxicity to normal prostate epithelial cells. Significant antiproliferative activity was observed, especially for Cytisus scoparius, Ononis arvensis, and Genista tinctoria, while most extracts reduced prostate-specific antigen (PSA) secretion in normal prostate cells. Furthermore, the extracts showed anti-inflammatory properties by reducing the pro-inflammatory cytokine interleukin 6 (IL-6) and improving cytokine balance indices. Multivariate analyses revealed correlations between total isoflavone content and antiproliferative activity. Full article

Background/Objectives: Glucocorticoids, including dexamethasone (DEX), are known to demonstrate anti-inflammatory activity, suppress steroidogenesis, and mitigate the adverse effects of chemotherapy. They are therefore widely employed for managing solid malignancies. Emerging evidence indicates that DEX modulates both systemic and local renin–angiotensin system (RAS) activity, including genomic signaling via the glucocorticoid receptor (GR). Methods: DEX-dependent transcriptional responses for the angiotensin receptor genes (AGTR1, AGTR2, MAS1, and LNPEP) were evaluated in ovarian (SKOV3, KURAMOCHI) and prostate (DU-145, PC3) cancer cell lines. The cells were cultured under different serum conditions to determine the influence of nutrient availability on tumor progression. Results: DEX demonstrated distinct mechanisms of action between the ovarian and prostate cancer models. It was found to promote cancer cell survival through tissue-specific modulation of metabolic activity, clonogenic capacity, cell cycle distribution, and apoptotic responses. These effects were accompanied by condition-dependent alterations in angiotensin receptor gene expression. Hence, DEX may mediate the remodeling of local RAS signaling, which may be significant in overall survival and disease-free survival. The findings also indicate a previously-unreported NR3C1–LNPEP correlation, which was consistently observed across in vitro systems and patient datasets, in both ovarian- and prostate-derived cancer models. Conclusions: DEX appears to exert context-dependent regulation of RAS-associated gene networks in ovarian and prostate cancer, suggesting a role in tumor adaptive responses and potentially in therapeutic contexts. Full article

Breast and prostate cancers remain among the most prevalent epithelial malignancies worldwide, and conventional treatments often lack tumor selectivity. Aloin, an anthraquinone glycoside derived from Aloe vera, has demonstrated promising anticancer properties. This study investigated the differential cytotoxic and apoptotic effects of Aloin under in vitro conditions in MCF-7 (breast cancer) and PC-3 (prostate cancer) cell lines compared with normal prostate epithelial cells (PNT-A1). Cells were treated with Aloin (1000–1500 µg/mL); cytotoxicity was assessed by CCK-8 assay, apoptotic morphology by DIC microscopy, protein expression by immunofluorescence with quantitative CTCF analysis (BAX, Caspase-3, Caspase-8, Caspase-9), and gene expression by qRT-PCR (2^−ΔΔCt method). An integrated log₂ fold change heatmap, pathway enrichment analysis across three independent databases (KEGG 2026, Reactome 2024, WikiPathways 2024), and STRING v12.0-based protein–protein interaction (PPI) network were constructed. Aloin exerted significant dose-dependent cytotoxicity in both cancer cell lines, while PNT-A1 viability exceeded 50% across all concentrations (Selectivity Index > 1.30 for MCF-7 at 48 h). Immunofluorescence and qRT-PCR confirmed significant upregulation of BAX (up to 6.14×), CASP8 (up to 15.51×), CASP9 (up to 9.27×), and CASP3 (3.03× in PC-3), indicating concurrent activation of intrinsic and extrinsic apoptotic pathways, while all genes remained unchanged in PNT-A1 cells. Pathway enrichment analysis confirmed that these genes are statistically central nodes in conserved apoptotic signaling networks (adj. p < 10⁻⁹). To the best of our knowledge, this is the first in vitro characterization of Aloin-induced pro-apoptotic activity in prostate cancer cells, establishing a mechanistic foundation for further investigation of this phytochemical in epithelial-derived cancer models. Full article

Castration-resistant prostate cancer (CRPC) remains a significant clinical challenge due to the ability of tumor cells to undergo intratumoral androgen synthesis, a process catalyzed by the CYP17A1 enzyme. The only CYP17A1 inhibitor available in therapy, abiraterone acetate, faces significant limitations due to its steroidal structure, which causes off-target effects and generates agonistic metabolites that paradoxically stimulate the androgen receptor (AR). This study presents the development of the D2AAK1M series, a novel class of non-steroidal potential CYP17A1 inhibitors based on a pyridine–piperidine scaffold. Through biomimetic design and molecular docking, we demonstrated that these compounds have the potential to coordinate the heme iron while achieving high shape complementarity within the catalytic pocket. In silico ADME profiling indicated superior physicochemical properties compared to abiraterone, including optimal lipophilicity, enhanced water solubility, and the potential to penetrate the blood–brain barrier for targeting CNS metastases. In vitro assay results correlated with a suggested mechanism, showing preferential cytotoxicity toward androgen-dependent LNCaP cells (AR+) while sparing AR-negative lines (DU145, PC3) and healthy human fibroblasts (BJ). Our compounds present a promising starting point for further development of non-steroidal CYP17A1 inhibitors. Full article

Surface modification of zinc oxide nanoparticles (ZnO NPs) with organosilane capping agents represents an effective strategy to control their physicochemical and biological properties. In this work, we report for the first time the use of halogenosilanes, namely (3-chloropropyl)trimethoxysilane (CPTMS), (3-bromopropyl)trimethoxysilane (BPTMS) and (3-iodopropyl)trimethoxysilane (IPTMS), for the surface functionalization of ZnO NPs obtained by chemical precipitation. Structural and morphological characterization (PXRD, TEM, SEM-EDX and FTIR) confirmed successful surface modification and revealed a significant particle size reduction from ~31 nm for unmodified ZnO to ~8 nm for BPTMS-modified ZnO (ZnO_b). The biological evaluation showed that halogenosilane-modified ZnO NPs exhibit enhanced cytotoxic activity against prostate cancer cell lines (PC3 and 22Rv1), with ZnO_b displaying the highest activity, likely associated with improved cellular uptake and increased reactive oxygen species (ROS) generation. In contrast, antimicrobial assays revealed only moderate bactericidal effects against Escherichia coli and Staphylococcus aureus at relatively high concentrations (≥1250 µg mL⁻¹), while no significant activity was observed against Pseudomonas aeruginosa, Burkholderia contaminans or Candida spp., within the tested range. These findings suggest that halogenosilane functionalization modulates the biological profile of ZnO nanoparticles by enhancing anticancer effects while also influencing microbiocidal activity, highlighting the role of surface chemistry in tuning biological selectivity. The present study supports the concept that rational surface engineering of ZnO-based nanoplatforms can be exploited to favor tumor-targeted activity over broad-spectrum antimicrobial effects, providing new perspectives for the design of application-oriented nanomaterials. Full article

Drug repurposing presents as a promising strategy in oncology, particularly for urological prostate and bladder cancers, where resistance to current therapy remains a challenge. This study evaluated the anticancer potential of three antiretroviral drugs, namely ritonavir (RIT), saquinavir (SAQ), and rilpivirine (RPV), in PC-3 and UM-UC-5 cancer cell lines, using MTT, clonogenic, wound healing, toxicity assessment with fibroblast cells, and DCFDA assays; this last method included efavirenz (EFV) and etravirine (ETV) for intracellular reactive oxygen species (ROS) production. RIT and SAQ showed stronger antiproliferative effects than RPV, with lower concentration- and cell-line-dependent activity, while clonogenic assays confirmed a reduction in long-term proliferation, particularly for RIT in both cell lines and SAQ for UM-UC-5. In contrast, effects on cell migration were limited for all drugs. ROS production was cell-dependent, with EFV increasing ROS in PC-3 and SAQ and RIT in UM-UC-5 cells. Generally, all drugs showed minimal toxicity in non-malignant cells, with SAQ exhibiting some toxicity but only for concentrations higher than those required for anticancer activity. Overall, these findings suggest that antiretroviral, especially protease inhibitors, may cause anticancer effects, although these are concentration- and context-dependent, and further investigation is needed to understand the mechanisms involved. Full article

Background: Minimum apparent diffusion coefficient (ADC) values are independent predictors of clinically significant prostate cancer (csPC). We developed a novel ADC-based bi-color map and evaluated its utility for identifying lesions suspicious for csPC. Methods: We retrospectively analyzed 108 targeted prostate biopsy cases and 93 radical prostatectomy cases. In the biopsy cohort, we assessed the association between ADC-based bi-color map positivity and csPC in lesions with a Prostate Imaging–Reporting and Data System (PI-RADS) score ≥ 3. In the prostatectomy cohort, we evaluated additional color map-positive lesions not categorized as PI-RADS ≥ 3 on preoperative MRI. Results: In the biopsy cohort, 118 lesions were positive on the ADC-based bi-color map, including lesions outside PI-RADS ≥ 3 categories. Among 157 lesions with a PI-RADS score ≥ 3, csPC was detected in 65 lesions (41.4%). Of these lesions, 70 (44.6%) were positive on the bi-color map, and csPC was identified in 49 (70.0%). The added value of the bi-color map was most evident in PI-RADS 4 lesions, where csPC detection rates were significantly higher in color map-positive than in color map-negative lesions (74.4% vs. 23.3%). In the prostatectomy cohort, 215 lesions were positive on the bi-color map, and csPC was confirmed pathologically in 126 lesions (58.6%). Among 82 color map-positive lesions not classified as PI-RADS ≥3, 55 (67.1%) corresponded to csPC. Conclusions: The ADC-based bi-color map may improve lesion highlighting and risk stratification for csPC and help identify suspicious lesions overlooked on conventional MRI assessment. Full article