Search Results (1,168)

Worldwide, prostate cancer (PC) has a rising incidence and is the sixth leading cause of death globally, especially with increasing cases in developing countries. Risk factors for PC include genetic predisposition, family history, race/ethnicity, and various occupational factors like diet, obesity, smoking, and transmitted diseases. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway can be activated by hormones, cytokines, and growth factors, and it plays a role in many vital biological processes such as cell growth, differentiation, immune regulation, and apoptosis. Dysregulation of JAK/STAT3 can lead to cancer, inflammation, diabetes, and neurodegenerative disorders. In cancers, including PC, STAT3 promotes cell survival, progression, angiogenesis, and metastasis. Inhibitors targeting JAK and STAT3 tested in vivo have shown potential to inhibit malignant cell growth. Additionally, flavonoids are bioactive plant compounds that are important in preventing inflammation, oxidative stress, and cancer. Research indicates that natural flavonoids can be developed into cancer-preventive and therapeutic agents. Experimental studies have demonstrated that some flavonoids can inhibit PC development. The main goal of this review is to present the incidence and risk factors of PC, the JAK/STAT3 pathway and its inhibitors, and how flavonoids may influence this pathology. Full article

Background: Although the relationship between androgen deprivation therapy (ADT) for prostate cancer (PC) and the biological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unequivocally unclear, it is possible that exposure to the virus may influence PC evolution by altering TMPRSS2 expression. This study aims to evaluate the long-term oncological outcomes of patients with metastatic PC who were undergoing medical therapy at the time of contracting SARS-CoV-2 and who resumed/continued anticancer treatment after recovery. Methods: We retrospectively evaluated a consecutive series of 151 metastatic PC patients who developed SARS-CoV-2 infection while receiving one active systemic anticancer therapy (125 metastatic castration-resistant PC (mCRPC) patients and 26 metastatic hormone-sensitive PC (mHSPC) patients). We evaluated variables that influence the ability to maintain or resume the ongoing therapy. For the maintained/resumed therapies, we calculated the post-infection overall survival (piOS) and the overall survival (OS). Results: Of the patients, 12.6% died due to SARS-CoV-2 infection, 10.6% recovered from the infection but failed to maintain/resume the ongoing anticancer treatment, and the remaining 76.8% maintained/resumed the treatment after recovery. Hospitalization, duration of infection, and the type of ongoing anticancer agent influenced these treatment changes. In the cohort of mCRPC patients, the median piOS was 32 months, and the median OS was 67.8 months. The median piOS was not achieved in the cohort of mHSPC patients, while the median OS was 122 months. The outcomes of single anticancer agents were in line with those of pivotal trials. Conclusions: Although observed in a highly selected population of PC patients who survived SARS-CoV-2 infection and were able to resume/maintain anticancer therapy, the survival outcomes of this study appear to be in line with those reported in pivotal studies, and SARS-CoV-2 infection does not seem to have adversely affected long-term oncological outcomes. Full article

Polydopamine (PDA) surface coatings are widely used in biomedical engineering to enhance cell–substrate interactions; however, their effects on cancer-cell behavior remain unclear. In this study, we investigated how PDA-coated two-dimensional (2D) culture surfaces influence oncogenic traits of human prostate cancer (PC) cells in vitro. Using LNCaP, DU145, and PC3 cell lines, we found that PDA-coated substrates markedly increased the adhesion, migration, invasion, proliferation, and colony formation in a dose- and time-dependent manner. PDA exposure also induced epithelial–mesenchymal transition (EMT), upregulated cancer stem cell markers (CD44, CD117, CD133, Sox2, Oct4, and Nanog), and elevated expression of metastasis- and chemoresistance-associated molecules (MMP-2, MMP-9, MDR1, and MRP1). Mechanistically, PDA coatings enhanced integrin α₂β₁-associated cell adhesion, accompanied by increased focal adhesion kinase (FAK) phosphorylation and downstream activation of JNK signaling. Pharmacological inhibition of integrin α₂β₁ (BTT-3033), FAK (PF573228) and JNK (SP600125) effectively abrogated PDA-induced malignant phenotypes and restored chemosensitivity to cabazitaxel, cisplatin, docetaxel, curcumin, and enzalutamide. Collectively, these findings identify PDA-coated surfaces as a simple, efficient, and reductionist in vitro platform for studying adhesion-mediated signaling and phenotypic plasticity in PC cells, while acknowledging that further validation in three-dimensional (3D) and patient-derived models will be required to establish in vivo relevance. Full article

Background/Objectives: Docetaxel is a widely used chemotherapeutic agent for several malignancies and is an established treatment for castration-resistant prostate cancer. However, its poor aqueous solubility, systemic toxicity, and the emergence of drug resistance limit its clinical benefit. Zein, a prolamin, forms micelles that enhance the solubility and delivery of hydrophobic drugs. As PEG length and ligand presentation govern micelle behavior, we investigated transferrin-functionalized PEGylated zein micelles as docetaxel nanocarriers and examined how PEG chain length (5 K vs. 10 K) and transferrin-mediated targeting affect delivery to prostate cancer cells. Methods: Docetaxel-loaded zein micelles bearing 5 K or 10 K PEG chains were prepared and conjugated to transferrin. Formulations were characterized for size, charge, morphology, critical micelle concentration, colloidal stability, drug loading and transferrin density. Cellular uptake and mechanisms were assessed in PC-3-Luc, DU145 and LNCaP cells by confocal microscopy, flow cytometry and pharmacological inhibition. Anti-proliferative activity was determined by MTT assays. Results: Both PEG5K and PEG10K micelles formed micellar dispersions with low polydispersity and high encapsulation efficiency. PEG5K micelles achieved higher transferrin conjugation and drug loading. Transferrin-functionalized PEG5K micelles showed enhanced uptake in DU145 and LNCaP cells but lower internalization in PC-3-Luc cells. Inhibitor studies indicated receptor-dependent uptake via clathrin- and caveolae-mediated endocytosis. Free docetaxel remained the most potent. However, among nanocarriers, transferrin-targeted PEG5K micelles showed the greatest anti-proliferative efficacy relative to their non-targeted counterparts, whereas transferrin-targeted PEG10K micelles were less potent than the non-targeted PEG10K micelles across all three cell lines. Conclusions: PEG chain length and ligand presentation are key determinants of uptake and cytotoxicity of docetaxel-loaded zein micelles. Shorter PEG chains favor effective transferrin display and receptor engagement, whereas longer PEG likely induces steric hindrance and reduces targeting, supporting transferrin-conjugated PEG5K zein micelles (the lead formulation in this study) as a targeted delivery platform that improves performance relative to matched non-targeted micelles in vitro, while free docetaxel remains more potent in 2D monolayer assays. Full article

A collection of 40 derivatives of 1,2-diphenyl-2-[1,2,3]triazol-1-yl-ethanol was obtained through a sequence of reactions, starting with benzoin as the initial raw material and using the CuAAC reaction as the key step in this process. The structure of a pair of these compounds was ultimately corroborated by single-crystal X-ray diffraction studies, which also reveals important O-H···N interactions. The antimicrobial activity of synthesized 1,2,3-triazoles was assessed against strains that include Candida albicans and Staphylococcus aureus. The antiproliferative properties of some of these novel compounds were also tested using a variety of tumor cell lines, including U251 (human glioblastoma), PC-3 (human prostate cancer cell line), K562 (human leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma), and SKLU (human lung adenocarcinoma). Full article

Cancer cells often have defects in antiviral pathways, making them susceptible to oncolytic viruses like vesicular stomatitis virus (VSV). However, some cancer cells resist viral infection through the constitutive expression of interferon-stimulated genes. This study examined whether NF-κB activation and NF-κB-dependent antiviral signaling contribute to resistance to VSV infection in the PC3 cell line, derived from an aggressive metastatic prostate cancer (PrCa) tumor. We found that NF-κB localized to the nucleus in VSV-infected PC3 cells, but not in the VSV-susceptible LNCaP PrCa cell line. Analysis of the upstream NF-κB inhibitor IκB-α revealed higher levels of both total and phosphorylated IκB-α in PC3 cells compared to LNCaP cells, indicating constitutive activation of the NF-κB pathway via an IκB-α-dependent mechanism. Notably, VSV infection did not alter IκB-α phosphorylation in PC3 cells, suggesting that VSV may amplify NF-κB signaling through an IκB-α–independent pathway. Furthermore, PC3 cells displayed elevated levels of the NF-κB p65 protein subunit compared to LNCaP cells, with its phosphorylated form significantly increased upon VSV infection. These results from phosphorylation assays confirm that multiple steps in the NF-κB pathway are differentially activated in PC3 and LNCaP cells. Finally, the expression of several NF-κB-dependent cytokines and proinflammatory genes, including IL12 and IL6, was upregulated following VSV infection in PC3 cells, as compared to LNCaP cells. Collectively, these findings suggest that enhanced NF-κB signaling may underlie the resistance of PC3 cells to VSV oncolysis, potentially offering new insights into therapeutic strategies targeting NF-κB in resistant prostate cancers. Full article

Disease heterogeneity across a diverse patient cohort poses challenges to cancer drug development due to inter-patient variability in treatment responses. However, current preclinical models fail to depict inter-patient tumor heterogeneity, leading to a high failure rate when translating preclinical leads into clinical successes. We integrated the expression profiles of prostate cancer (PC) lines and castration-resistant PC (CRPC) patient tumors to identify cell-lines that transcriptomically match distinct tumor subtypes in a clinical cohort. Representative cell-lines were co-cultured to create “mixed-cell” models depicting inter-patient heterogeneity in CRPC, which were employed to assess drug combinations. When drug combinations previously tested in CRPC clinical cohorts were assessed to establish proof of concept, in vitro responses measured in our models concurred with their known clinical efficacy. Additionally, novel drug combinations computationally predicted to be efficacious in heterogeneous tumors were evaluated. They demonstrated preclinical efficacy in the mixed-cell models, suggesting they will likely benefit heterogeneous patient cohorts. Furthermore, we showed that the current practice of screening cell-lines/xenografts separately and aggregating their responses, failed to detect their efficacy. We believe that the application of our models will enhance the accuracy of preclinical drug assessment, thereby improving the success rate of subsequent clinical trials. Full article

Introduction: Metabolomics-based phylogenetic profiling of prostate cancer (PCa) patients before and after stereotactic body radiation therapy (SBRT) can provide insight into the way in which treatment outcomes relate to the underlying physiology and physiological responses of individual patients. It also offers the potential for helping identify precision biomarkers. Methods: In this study, we used integrated mass spectrometry to obtain untargeted serum metabolomics data from PCa patients (n = 55), which we then analyzed using a parsimony phylogenetic systems biology approach before correlating the results with the patients’ clinical parameters before and after treatment. Results: Radiotherapy (RT) generated five phylogenetic subgroups with distinct metabolomic profiles that did not correspond to hormonal treatment, risk assessment, metastasis, or PSA levels. PSA was neither a factor influencing clade membership nor an indicator of risk assessment or metastasis. Moreover, the hormone-treated patients did not form their own clade but were rather spread among the five clades. The same absence of correlation applied to risk assessment and metastasis. The 88 significantly altered pre-RT and 29 post-RT features showed aberrations in the metabolic pathways of purines, porphyrin, glycerophospholipids, and 2-methylglutaric acid, among others. Discussion: Significantly altered metabolites in a majority of patients who developed metastasis included D-tryptophan, carbamate, 5′-Benzoylphosphoadenosine, Phosphatidylcholine (PC), bilirubin, and hypoxanthine. In general, the cladogram offers a new perspective on evaluating the clinical variables that represent significant indicators of PCa progression, metastasis, and treatment response in individuals. Conclusions: Metabolic profiles and associated clinical phenotypes provided by this precision phylometabolomics approach may offer a deeper understanding of the metabolic factors and pathways implicated in cancer progression and metastasis and should contribute to the development of targeted treatments and more precise monitoring of cancer and cancer therapies. Full article

Background: Prostate cancer remains a major contributor to cancer-related morbidity and mortality worldwide, emphasizing the need for safer and more effective therapeutic options. Andrographolide, a diterpenoid lactone derived from Andrographis paniculata, has shown promising anticancer activity, yet its effects on microRNA (miRNA) regulation in prostate cancer remain insufficiently explored. Methods: In this study, we evaluated the cytotoxic and molecular effects of andrographolide on two human prostate cancer cell lines, PC3 and LNCaP, along with HEK-293 cells as a noncancerous model. Results: Cell viability assessment using the MTT assay revealed dose-dependent cytotoxicity, with 24 h IC₅₀ values of 82.31 µM for PC3, 68.79 µM for LNCaP, and 133.9 µM for HEK-293 cells. Subsequent expression analysis of key oncogenic and tumor suppressor miRNAs demonstrated that andrographolide induced the upregulation of miR-16-5p, miR-34a-5p, and miR-200a-5p miRNAs implicated in apoptosis, proliferation control, and androgen receptor signaling. In contrast, the expression of oncomiRs miR-21-5p and miR-221-5p showed minimal or nonsignificant changes, reflecting the complex and context-specific roles of miRNAs in prostate cancer. Gene expression profiling further indicated differential transcriptional responses between the two prostate cancer cell lines, consistent with their distinct molecular backgrounds. Conclusions: Although HEK-293 cytotoxicity and previously reported nephrotoxic effects warrant caution, these results support the potential of andrographolide as an adjuvant phytochemical capable of modulating clinically relevant miRNAs in prostate cancer. Future studies investigating optimized delivery systems and validating direct miRNA targets may help advance andrographolide toward safer and more targeted therapeutic applications. Full article

Background/Objectives: A promising anticancer strategy is the simultaneous inhibition of the receptor tyrosine kinases VEGFR-2 and c-Met, which are essential for tumor angiogenesis, growth, and metastasis. In this study, a novel series of piperidinyl-based benzoxazole derivatives was designed and synthesized as potential dual VEGFR-2/c-Met inhibitors. Methods: The kinase inhibitory potential of the derivatives was evaluated in comparison to reference inhibitors, Sorafenib (VEGFR-2 inhibitor) and Staurosporine (c-Met inhibitor). Cytotoxicity was assessed across breast, prostate (PC-3), and lung (A549) cancer cell lines. Mechanistic studies included cell-cycle analysis, apoptosis assays, gene expression profiling of apoptosis-related markers, and molecular docking within the ATP-binding pockets of both kinases. Results: Compounds 5a, 5g, 5h, 11a, and 11b showed strong inhibition of both kinases (IC₅₀ = 0.145–0.970 μM for VEGFR-2 and 0.181–1.885 μM for c-Met). Selective cytotoxicity was observed against breast cancer cells, with compound 11b (p-fluorophenyl derivative) exhibiting high selectivity toward MCF-7 over normal breast cells (MCF-10A) and potency comparable to or exceeding Sorafenib. Mechanistically, 11b induced G₂/M cell-cycle arrest and apoptosis (total apoptosis = 48.34%), accompanied by upregulation of p53, BAX, and caspase-9 and downregulation of Bcl-2. Molecular docking confirmed stable binding within the ATP-binding sites of both kinases. Conclusions: Compound 11b was established as a novel, selective, dual VEGFR-2/c-Met inhibitor with strong potential for targeted breast cancer therapy. Full article

Castration-resistant prostate cancer presents radiotherapeutic challenges, especially in optimizing the cytosolic internalization of therapeutic radiopharmaceuticals. This research aimed to design and evaluate in vitro, a new dimeric radiopharmaceutical, [¹⁷⁷Lu]Lu–iPSMA–iGRP78, which combines PSMA and GRP78 inhibitors in a heterodimeric radioligand to improve the radionuclide internalization and cytotoxicity efficacy. Molecular docking showed that the dimer iPSMA–iGRP78 presents a higher affinity for GRP78 (CNN-docking score: −14.0 kcal·mol⁻¹, pKi: 10) and for PSMA (CNN-docking score: −17.0 kcal·mol⁻¹, pKi: 11.5) compared to the monomers iGRP78 (CNN-docking score: −11.0 kcal·mol⁻¹, pKi: 9.4) and iPSMA (CNN-docking score: −13.9 kcal·mol⁻¹, pKi: 10.2). The saturation binding assay using LNCaP cells (PSMA+, CS-GRP78+) showed an affinity (K_d) of 1.883 nM for [¹⁷⁷Lu]Lu–iPSMA–iGRP78 and 2.245 nM for [¹⁷⁷Lu]Lu–iPSMA. The dimeric radiopharmaceutical achieved 10.44 ± 2.43% cytosolic internalization and 4.81 ± 0.94% nuclear internalization, while the [¹⁷⁷Lu]Lu–iPSMA monomer showed 6.45 ± 0.60% cytosolic internalization and no uptake in the cell nucleus. In PC3 cells (PSMA–, CS-GRP78–), [¹⁷⁷Lu]Lu–iPSMA–iGRP78 uptake was negligible, demonstrating specificity. Treatment with the dimeric radiopharmaceutical reduced cell viability (69.93 ± 4.85% of dead cells) significantly more than [¹⁷⁷Lu]Lu–iPSMA (38.63 ± 6.13% of dead cells). In conclusion, conjugation of a GRP78 inhibitor to [¹⁷⁷Lu]Lu–iPSMA improves the radionuclide internalization and cytotoxicity in prostate cancer cells, suggesting that the bispecific radiopharmaceutical is a promising strategy in prostate cancer treatment. Full article

Background/Objectives: The genitourinary microbiome and metabolome may contribute to prostate cancer (PC) biology, but evidence remains limited. This pilot study characterizes the urinary microbiota and volatilome in men with PC and investigates microbial and viral DNA in prostate tissue, comparing findings with benign prostatic hyperplasia (BPH). Methods: We prospectively enrolled 21 non-metastatic PC patients undergoing radical prostatectomy and 17 BPH controls. Lesional and non-lesional prostate tissues and urine were collected from PC patients, as well as urine samples from BPH participants. DNA samples were tested for sexually transmitted pathogens by multiplex real-time PCR. Urine and prostate tissue were analyzed for human polyomaviruses (JCPyV, BKPyV, MCPyV) by qPCR, bacterial profiles via 16S rRNA gene sequencing, and urinary volatile organic metabolites (VOMs) using HS-SPME/GC-MS. Microbial and metabolic profiles were compared, and taxa–metabolites were assessed. Results: JCPyV and BKPyV were detected in urine and tissue from PC patients; MCPyV was detected only in tissue, at low frequency. In BPH, viral prevalence was lower and MCPyV was absent. JCPyV/BKPyV co-infection was common in cancer. No sexually transmitted pathogen emerged. PC patients showed greater urinary microbial diversity and five enriched genera, along with specific metabolic pathways. 36 urinary VOMs were identified, with 14 differing significantly, with positive correlations between PC-associated genera and metabolites. In contrast, prostate tissue was low-biomass, dominated by Pseudomonas, and showed no significant differences between lesional and non-lesional areas. Conclusions: This preliminary, hypothesis-generating study indicates that urinary, rather than tissue, microbial and volatilome signatures show clearer differences between PC and BPH. These findings suggest possible microbiota–metabolite interactions in PC but require validation in larger cohorts. Full article

Background/Objectives: Multiparametric MRI (mpMRI) and targeted biopsies have revolutionized prostate cancer (PC) detection through the Prostate Imaging Reporting and Data System (PIRADS). However, the effect of prostate volume on cancer detection and the predictive accuracy of PIRADS in the mpMRI-guided biopsy era remains unclear. The aim was to assess whether prostate volume affects detection rates of clinically significant prostate cancer (CSPC) and high-risk prostate cancer (HRPC) and modifies the predictive performance of the PIRADS score. Methods: We retrospectively analyzed 361 biopsy-naïve men who underwent mpMRI-fusion transperineal biopsies between 2016 and 2023. Lesions graded PIRADS ≥ 3 were targeted alongside systematic sampling. A receiver-operating characteristic (ROC) curve (AUC = 0.74) defined a 44 mL cutoff separating small (<44 mL; n = 160) and large (≥44 mL; n = 193) prostates. Logistic regression and cubic-spline analyses evaluated associations between prostate volume, PIRADS, and cancer outcomes. Results: Any cancer was detected in 74.3% of small versus 35.5% of large prostates (p < 0.001); CSPC in 42.5% vs. 19.6% (p < 0.001); HRPC in 14.3% vs. 5.5% (p < 0.001). Small prostate volume independently predicted any cancer (OR 7.31; 95% CI 4.22–12.7), CSPC (OR 5.08; 95% CI 2.87–8.99), and HRPC (OR 4.50; 95% CI 1.80–11.3). Between 40 and 70 mL, each 10 mL increase in volume reduced CSPC risk by 61% (p = 0.008). Prostate volume significantly modified PIRADS accuracy: in large glands, PIRADS 3 lesions carried only 2% risk for CSPC and 0% for HRPC, while in small prostates, PIRADS 3 conferred a 16.9-fold increased CSPC risk. Conclusions: Prostate volume inversely correlates with cancer detection and aggressiveness. PIRADS performance is volume-dependent; PIRADS 3 lesions in large prostates rarely represent significant cancer and may not warrant biopsy. Full article

Prostate cancer (PC) remains a major cause of cancer deaths in men. The serum biomarker prostate-specific antigen (PSA) lacks specificity in distinguishing clinically significant PC (sPC) from insignificant PC (isPC), leading to overdiagnosis and overtreatment. Although magnetic resonance imaging (MRI) improves detection, it is expensive, is time-consuming, and may involve inter-reader discrepancies. Recently, metabolomics, which has a high analytical sensitivity and broad molecular-feature coverage, has emerged as a promising tool to risk-stratify PC. This review examined studies of blood and urine metabolomics for sPC biomarker identification. Significant metabolite changes in sPC patients often involved fatty acid metabolism, sphingolipid metabolism, glycolysis, the citric acid cycle, purine/pyrimidine metabolism, and tyrosine/phenylalanine metabolism. Specifically, more than one study reported increased lactate and phenylalanine levels, along with decreased tyrosine, xanthine, and histidine levels, in sPC patients. Several metabolic panels outperformed serum PSA in predicting sPC, particularly when combined with clinical factors. Among these, two urine-based tests may have higher accuracy in predicting sPC than most current commercially available assays. However, direct comparison between studies may be inappropriate due to methodological heterogeneity, the variability in biospecimen types, inconsistent use of digital rectal examinations, and different sPC definitions and predictive endpoints. Most relevant studies were of small sample size or lacked external validation. Despite these challenges, metabolomics-based liquid biopsies show strong potential for improving sPC detection. Future research should focus on protocol standardization, MRI integration, absolute metabolite quantification, and validation in large and independent cohorts to enhance model credibility. Full article

Background/Objectives: Cancer survivors are a growing population in the United States, with projections of 22.5 million by 2030. Cancers of the prostate (PC) and breast (BC) are among the most prevalent. Despite a high burden of disease, African American survivors are underrepresented in health behavior research. Leveraging two large databases, this study uniquely characterizes dietary supplement (DS) use among African American cancer survivors to explore potential intervention points. Methods: Characteristics from 376 African American cancer survivors (130 PC; 246 BC) in lifestyle intervention trials were examined. DS use was self-reported and categorized by type. A logistic regression model examined associations between use and survivor characteristics. Results: Overall, 215 (63.80%) survivors with baseline medication log data (N = 337) reported using at least one DS, with a higher prevalence among BC survivors (67.44%) than PC survivors (57.38%). Vitamin D ± calcium combinations, multivitamins, omega-3 fatty acids, calcium, Vitamin B12, and Vitamin C were the most frequently reported. Total comorbidities (mean = 2.38, SD = 1.66) significantly predicted increased DS use among BC and PC survivors. Educational attainment (≤12th grade vs. graduate/professional education) and diet quality (high vs. low) were significantly associated with lower odds of DS use for PC survivors. Only diet quality (moderate vs. low) was significantly associated with higher odds of DS use in BC survivors. Conclusions: DS use is common among African American PC and BC survivors participating in lifestyle interventions. These findings underscore the need for evidence-based guidelines regarding DS use among cancer survivors and the need to include diverse populations. Full article