Prostate cancer remains the second most common cancer among men around the world, with 1.4 million new cases annually. Treatment resistance and off-target toxicity require innovative therapeutic approaches. Natural compounds such as eugenol exhibit anticancer potential, but poor pharmacokinetic properties constrain clinical application. This study evaluated the cytotoxic, apoptotic, and pharmacokinetic properties of three eugenolderived allyl phenol compounds (38, 42, 47), previously recognized as potent 15-lipoxygenase-1 (15-LOX-1) inhibitors, in prostate cancer models. The cytotoxic activity was evaluated in PC-3 prostate cancer cells and Human Dermal Fibroblasts (HDF) using AlamarBlue assays, flow cytometry, and morphological analysis. Computational validation involved Density Functional Theory (DFT) calculations, molecular docking into 15-lipoxygenase-1 (15-LOX-1; PDB: 2P0M), and structural analysis. Pharmacokinetic and toxicity profiles were predicted in silico using SwissADME, pkCSM, and ProTox-III platforms. All three compounds were cytotoxic to PC-3 cells in a concentration-dependent way with some selectivity for normal cells. Apoptosis was confirmed by increased sub-G1 peak and morphological changes, while BAX or BCL-2 mRNA levels did not change. In silico studies (DFT and docking) showed that the compounds bound well to 15-LOX-1 (docking scores: -6.6 to -7.3 kcal/mol), with compound 42 having the strongest binding affinity. Structural analysis showed that the proteins were moderately flexible (B-factor: 47.45 ± 13.07 Ų), which supports stable ligand accommodation. Computational ADME/toxicity predictions suggested generally favorable pharmacokinetic profiles; however, compound 42 was poorly soluble, and compound 47 was identified as a P-gp substrate, indicating a potential efflux liability. The pro-apoptotic effects observed despite unaltered BAX and BCL-2 mRNA levels indicate that the apoptotic response is likely mediated through mechanisms other than transcriptional regulation of these genes, potentially by blocking 15-LOX-1. Computational modeling indicated that all three compounds can effectively bind to the 15-LOX-1 active site, and their binding affinities are in line with their experimental inhibitory potencies (IC50: 0.80-0.88 μM). The integration of in vitro and in silico results confirms the therapeutic potential of these compounds and underscores the necessity for additional mechanistic studies and in vivo evaluation. These results highlight the anticancer properties of eugenol-derived allylphenol compounds. The compounds induce apoptosis by mechanisms independent of BAX/BCL-2 transcriptional modulation. Computational modeling suggests potential involvement of 15-LOX-1; nevertheless, direct mechanistic validation via caspase activity, ROS generation, or protein-level quantification of BAX/BCL-2 is necessary to verify the apoptotic pathway. The compounds suggest favorable pharmacokinetic profiles along with strong enzyme binding characteristics. Compound 38 exhibited the most balanced profile, characterized by high cytotoxicity, selectivity, and predicted ADME properties. Additional mechanistic investigations and in vivo validation are necessary to advance these candidates through preclinical development.

Natural products are rich therapeutic sources, yet their translation into effective medicines remains challenging. Bee venom (BV) contains a diverse repertoire of bioactive molecules, but gentle, scalable methods to enhance its functionality are limited. This study, therefore, investigates a novel, solvent-free, post-extraction infrared (IR) conditioning step to fine-tune BV's composition and bioactivity. BV was irradiated (230V, 50Hz, 150W) and compared to native extract using GC-MS and bioactivity assays. GC-MS revealed selective compositional tuning, with significant enrichment (p ≤ 0.05) of 4H-1-benzopyran-4-one, 2-(3,4-dimethoxyphenyl)-3,5-dihydroxy-7-methoxy. IR-treated BV exhibited enhanced antimicrobial activity, with increased zones of inhibition forStaphylococcus aureus(15 ± 0.1 vs. 11 ± 0.4mm),Bacillus subtilis(24 ± 0.2 vs. 22 ± 0.6mm),Candida albicans(26 ± 0.1 vs. 22 ± 0.5mm),Klebsiella pneumoniae(24 ± 0.4 vs. 15 ± 0.3mm), andSalmonella typhi(27 ± 0.8 vs. 20 ± 0.7mm). MICs decreased forS. aureus,B. subtilis, andK. pneumoniae. The treated BV also showed stronger antibiofilm activity at 25% MBC concentrations for K. pneumoniae and S. typhi (p ≤ 0.05) and significantly reduced hemolysis at 25% MIC for S. aureus and B. subtilis (p ≤ 0.05). Antioxidant capacity increased (DPPH IC50: 16.47 ± 1.1 vs. 27.65 ± 0.8µg/mL), as did anti-inflammatory activity (COX-2 IC50: 48.84 ± 0.2 vs. 50.99 ± 0.9µg/mL; COX-1 IC50: 24.7 ± 0.2 vs. 41.74 ± 0.2µg/mL). Cytotoxicity against PC-3 and SKOV-3 cells was maintained (IC50: 19.73 ± 0.9 and 19.76 ± 0.11µg/mL, respectively, vs. native BV's 11.48 ± 0.3 and 17.46 ± 0.27µg/mL). These findings establish brief IR irradiation as a practical, scalable post-processing strategy to selectively enhance the therapeutic potential of BV for biomedical applications.

Targeted payload release in cancer cells can be modulated by tuning both the linker, spacer, and the payload chemistries. In previous studies, a PSMA-targeted probe incorporating a 7-amino-4-methylcoumarin (AMC) payload and a PEG linker resulted in predominant payload release in the lysosome (pH ∼5.0). Here, we introduce a second-generation PSMA-targeted turn-on probe with a shorter, hydrophobic linker and a 7-hydroxy-4-methylcoumarin (HMC) payload. Based on pH-dependent kinetic studies, the HMC payload exhibits faster cleavage at a slightly higher pH (pH5.5), suggesting an earlier release-potentially more in early endosomes than lysosomes. Our results demonstrate that subtle changes in linker and payload structures can alter intracellular release kinetics, offering improved control over the cellular release site, which is critical for optimizing targeted therapeutic and imaging strategies in prostate cancer cells.

Background/Objectives: The G protein-coupled oestrogen receptor (GPER) has anti-tumorigenic effects in several human cancers. However, its role in prostate cancer (PCa) remains incompletely defined. The present study investigated GPER's role in targeting the hallmarks of PCa. Methods: Tissue microarrays were used to analyse GPER immunoexpression in PCa samples. Non-neoplastic (PNT1A) and neoplastic (LNCaP, DU145 and PC3) prostate cells were treated with the GPER-specific agonist, G1. Cell viability, proliferation, cell cycle, apoptosis, migration and invasion were evaluated. Glucose consumption, lactate production, lactate dehydrogenase activity and oxidative status were determined spectrophotometrically. Results: GPER immunoreactivity was higher in PCa than in benign prostatic hyperplasia and inversely correlated with PSA serum levels. G1 modulated GPER subcellular location in prostate cells, being detected at the cell membrane, endoplasmic reticulum, and residually in the nucleus. GPER activation decreased cell viability and proliferation, induced cell cycle arrest at G2/M phase, and increased PCa cells apoptosis. Additionally, GPER activation inhibited the migration and invasion of DU145 cells, and long-term exposure to G1 reduced epithelial-mesenchymal transition, an effect not observed in PC3 cells, indicating the importance of cell-specific contexts. Our results also showed that G1 treatment modulated the metabolic profile of PCa cells, changing glucose, amino acids and lipid metabolism. Finally, G1 increased oxidative stress in PCa cells. Conclusions: Overall, this study demonstrated that GPER activation affects a broad range of PCa hallmarks. These findings support an anti-cancer role for GPER in PCa and encourage further exploration of its action in regulating metabolism and as a therapeutic target.

Prostate cancer (PCa) is the second most common cancer and second leading cause of cancer death for American men. Chemoprevention by using phytochemicals offers a promising approach to improve outcomes due to their ability to act on cancer cell metabolism and growth while maintaining low toxicity profiles. The goal of this study was to assess the combination of xanthohumol (XAN) and ursolic acid (UA) given in the diet for synergistic efficacy against PCa progression and identify potential mechanisms of action. PCa cells were treated with the combination to evaluate cell survival and colony formation. Two mouse models of PCa were used to evaluate tolerability and efficacy of dietary administration of the combination and to further understand mechanism(s) of action. The combination of XAN + UA reduced PCa cell survival and colony formation. The combination given in the diet significantly and synergistically inhibited growth of HMVP2 PCa allograft tumors and also inhibited PCa progression in HiMyc mice. Mechanistically, inhibition of polyamine synthesis and epithelial-to-mesenchymal transition contributed to the inhibition of HMVP2 allograft tumor growth, while the inhibition of PCa progression in HiMyc mice was associated with activation of the unfolded protein response pathway and apoptosis. Further studies in cultured PCa cells revealed additional effects of the combination on several oncogenic signaling pathways (e.g, phospho-STAT3) and cell cycle regulatory proteins (e.g, cyclin D1, phospho-Rb).

Treatment of locally advanced and metastatic prostate cancer (PC) with androgen receptor–targeting (AR-targeting) therapies has limited durability, with disease eventually progressing to castrate-resistant PC (CRPC). Constitutively active AR splice variants (AR-Vs), such as AR-V7, play a key role in driving treatment resistance and disease progression. Importantly, the failure to attenuate AR-V function represents a major unmet clinical need, and as such, defining how AR-Vs are generated is likely to yield new therapeutic targets. Our knowledge of factors that mediate splicing of AR-V–encoding mRNAs remains limited. Here, we have employed an RNA-targeting CasRx approach to identify selective protein interactors of AR-V7 mRNA in PC. TRA2B and its ortholog, TRA2A, were identified as splicing regulators of AR transcripts that facilitate AR-V synthesis at the expense of full-length AR isoforms. TRA2B expression correlated with AR-V7 transcript in CRPC and attenuation of TRA2-mediated splicing diminished PC cell growth. Exploiting TRA2B function may therefore provide new therapeutic opportunities in advanced disease.

Targeting glycolysis in prostate cancer: Molecular mechanisms and therapeutic advances.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PCa), associated with poor prognosis and resistance to androgen receptor (AR)‑targeted therapies. Hypoxia is a well‑established driver of lineage plasticity and has been implicated in promoting NE differentiation (NED) of tumors. However, the underlying molecular mechanisms linking hypoxia to NED remain unclear. In the present study, miR‑135b‑5p was identified as a critical regulator of hypoxia‑induced NED through modulation of the hypoxia‑inducible factor alpha‑1 subunit alpha inhibitor (HIF1AN)‑HIF1α axis. Exposure of androgen‑dependent PCa cell lines (LNCaP and VCaP) to hypoxia induced neurite outgrowth and increased expression of NE markers, concurrent with upregulation of miR‑135b‑5p. Target prediction followed by experimental validation in luciferase reporter assays confirmed that HIF1AN is a direct target of miR‑135b‑5p. Suppression of HIF1AN results in the stabilization of HIF1α, which in turn activates the AKT/mTOR signaling pathway, facilitating NE trans differentiation. Functional studies demonstrated that overexpression of miR‑135b‑5p by mimics promotes NED in LNCaP cells, while inhibition of miR‑135b‑5p reverses the NE features in NE‑LNCaP and NCI‑H660, NE cells. Furthermore, pharmacological inhibition of HIF1α using PX‑478 abrogated hypoxia‑induced NED and attenuated activation of AKT/mTOR signaling, further underscoring the significance of the miR‑135b‑5p‑HIF1AN‑HIF1α axis in NED of PCa cells. Collectively, the findings of the present study reveal a novel miR‑135b‑5p‑HIF1AN‑HIF1α signaling axis that is involved in hypoxia‑induced NED via AKT/mTOR activation and identify miR‑135b‑5p and HIF1α as potential therapeutic targets for NEPC.

The high mortality rates of prostate cancer correlate with patients who are diagnosed with bone metastasis. We have fabricated an innovative bioreactor with an injection port ideal for recapitulating the EMT (epithelial to mesenchymal transition) to MET (mesenchymal to epithelial transition) cascade of circulating prostate cancer cells. Further, the migration to bone by hypoxic cancer cells was evaluated under fluid flow. First, we demonstrated that hypoxia, an initiator of metastasis, activates αVβ3 integrins, leading to enhanced cell attachment and growth. We assessed the expression of αVβ3 and the MET biomarkers vimentin and E-cadherin to evaluate role of interstitial fluid flow on circulating prostate cancer cells. We observed upregulation of αV, β3, and E-cadherin expression in normoxic and hypoxic PC3 cells. Hypoxic PC3 cells expressed higher angiogenic markers such as VEGF (vascular endothelial growth factor), MMP-9 (matrix metalloproteinase protein-9), and FAK (focal adhesion kinase). We recapitulated the migration of clustered cells using hanging drop spheroids and observed different migratory pattern and that the crosstalk between PC3 cells and cancer-associated-fibroblasts alters the angiogenicity of cancer spheroids. Overall, this study showcases the ability of this bioreactor to mimic prostate cancer migration to bone under interstitial fluid flow. Understanding the migratory patterns of metastatic prostate cancer can help in predicting cancer progression and identifying appropriate therapies for patients with advanced-stage prostate cancer.

Development and evaluation of choline tagged mesoporous silica nanoparticles for targeted delivery and imaging in prostate cancer.

Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p/STING/LGALS1 pathway.

Ginsenoside Rg3 synergizes with near-infrared photothermal therapy to suppress prostate cancer progression by inhibiting RAS signaling and enhancing ARL11-mediated macrophage reprogramming.

In this study, a series of novel iridium(III) complexes incorporating 2-phenylimidazo[4,5-f][1,10]phenanthroline ligands with different substituents (methyl (1a), isopropyl (2a), methoxy (3a), phenyl (4a)) were evaluated for their in vitro inhibitory activities against anticholinesterase (acetylcholinesterase [AChE], butyrylcholinesterase [BChE]) and carbonic anhydrase [hCA I] and [hCA II]) enzymes. Among the tested compounds, 2a demonstrated exceptional potency with IC50 values of 66.5 ± 9.06 nM for AChE and 26.45 ± 5.00 nM for BChE, significantly outperforming tacrine. Compound 4a also exhibited strong inhibition of hCA I (IC50 = 33.0 ± 7.09 nM) and hCA II (IC50 = 41.79 ± 8.09 nM), surpassing the reference drug acetazolamide. Molecular docking studies revealed that compound 4a exhibited the strongest binding affinity with BChE (PDB: 4BDS) at -12.06 kcal/mol, while compound 2a showed strong binding to hCA II (PDB: 3HS4) at -8.768 kcal/mol. Molecular dynamics simulations over 150 ns confirmed the structural stability of the protein-ligand complexes. Cell viability assays showed that compounds 1a-4a decreased PC3 prostate cancer cell viability in a concentration-dependent manner, with IC50 values of 10.09, 3.95, 11.39, and 4.51 µM, respectively. This comprehensive study highlights iridium(III) complexes as multitarget therapeutic agents with potent anticholinesterase and carbonic anhydrase inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders.

M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells.

Mechanism of benzophenone-3 in promoting proliferation and migration of prostate cancer cells via the acyl-CoA dehydrogenase 9 axis.

This study elucidates the critical role of adenosine A2A receptor (A2AR) signaling in prostate cancer progression through comprehensive molecular characterization and clinical validation, demonstrating that A2AR overexpression in prostate cancer cells drives profound immunosuppression via coordinated upregulation of CD73-mediated adenosine production, subsequent activation of immunosuppressive pathways including ARG1, TGF-β, and IL-10 secretion, and induction of immune checkpoint molecules PD-L1 and Galectin-9, which collectively promote myeloid-derived suppressor cell expansion and CD8+ T cell exhaustion while creating an immunologically privileged tumor microenvironment. Clinical correlation analyses across multiple patient cohorts reveal that elevated A2AR expression serves as a powerful independent predictor of aggressive disease progression and poor clinical outcomes, particularly in metastatic castration-resistant prostate cancer, where it exhibits stronger prognostic value than in other solid tumors. A2AR activation not only helps tumors resist immune checkpoint inhibitors but also blocking A2AR can work well with PD-1/PD-L1 treatments by reversing the immune suppression caused by adenosine and boosting the body's ability to fight tumors. The potential for using these findings in real-world clinical settings is backed by models showing that combining A2AR expression with adenosine pathway activity and immune profiling greatly improves the accuracy of risk assessment compared to standard prognostic markers, while earlier studies show that targeting this pathway could be a viable treatment option. These results collectively position A2AR as a master regulator of prostate cancer immunosuppression and a promising biomarker-guided therapeutic target, particularly for combination immunotherapy approaches in advanced disease settings where current treatment options remain limited.

Discovery of novel indole derivatives as LRH-1 antagonists for the treatment of castration resistant prostate cancer.

Effect of proton therapy and chemoradiotherapy on biochemistry of radioresistant prostate cancer cells studied by Raman microspectroscopy.

Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss.

Arachidonic acid analog AACOCF3 suppresses cPLA2-negative NSCLC cell proliferation by targeting SSRP1 to activate the IFNα/β pathway.