PC-3 Prostate Cancer Cells Research Articles

A pharmacoinformatic approach for studying Atractylodes Lancea DC’s anticancer potential and control ROS-mediated apoptosis against prostate cancer cells

IntroductionProstate cancer (PCa) is a malignancy characterized by abnormal cell proliferation in the prostate gland, a critical component of the male reproductive system. Atractylodes lancea DC. (ALD), a medicinal herb commonly used in traditional Asian medicine, is highly regarded for its antioxidant, antidiabetic, and anticancer properties. Virtual docking stud-ies have identified Atractylenolide II and III as active components of ALD, demonstrating strong binding potential to inhibit androgen receptor (AR) activity, with docking scores of -8.9 and -9.3, respectively. These findings suggest that ALD may exert a synergistic effect comparable to or greater than that of enzalutamide (ENZ) in inhibiting AR. How-ever, its specific anticancer and anti-metastatic mechanisms in prostate cancer remain unclear.MethodsThe cytotoxic effects of ALD were evaluated on PC3 and DU145 prostate cancer cells, as well as on the normal prostate cell line BPH-1. Cell viability was assessed using the EZ-Cytotoxic kit, while colony formation assays and TUNEL staining were used to meas-ure proliferation and apoptosis, respectively. Apoptosis was further analyzed through an-nexin V-FITC/PI staining and quantified by flow cytometry (FACS). Western blotting was performed to elucidate the underlying molecular mechanisms. Additionally, mito-chondrial membrane potential (ΔΨm) and intracellular calcium levels were measured to evaluate mitochondrial function, while reactive oxygen species (ROS) generation was assessed with and without pretreatment with N-acetylcysteine (NAC) .ResultsALD selectively reduced the viability of PC3 and DU145 prostate cancer cells while spar-ing BPH-1 normal prostate cells, demonstrating cancer-selective cytotoxicity. ALD dis-rupted mitochondrial function by reducing ΔΨm and increasing intracellular calcium lev-els. A concentration-dependent increase in ROS generation was observed in PC3 and DU145 cells, which was completely inhibited by NAC pretreatment, confirming a ROS-mediated mechanism. Colony formation assays revealed a significant reduction in prolif-eration, while TUNEL and annexin V-FITC/PI staining indicated enhanced apoptosis. Western blot analysis showed that ALD modulates critical survival pathways, leading to apoptotic cell death.DiscussionThese findings demonstrate that ALD exerts potent anticancer effects against metastatic prostate cancer cells through ROS-mediated apoptosis and mitochondrial dysfunction, while exhibiting minimal cytotoxicity toward normal prostate cells. The presence of ac-tive compounds such as Atractylenolide II and III suggests a synergistic interaction that enhances AR inhibition and promotes apoptosis. ALD’s ability to engage multiple path-ways highlights its therapeutic potential as a selective and multifaceted treatment for ag-gressive prostate cancer.

Impact of UV-Irradiated Mesoporous Titania Nanoparticles (mTiNPs) on Key Onco- and Tumor Suppressor microRNAs of PC3 Prostate Cancer Cells

Background: Mesoporous titanium dioxide nanoparticles (mTiNPs) are known for their chemical stability, non-toxicity, antimicrobial and anticancer effects, as well as for their photocatalytic properties. When this material is subjected to UV radiation, its electronic structure shifts, and during that process, reactive oxygen species are generated, which in turn exert apoptotic events on the cancer cells. Objectives: We evaluated the cytotoxic effects of UV-irradiated mTiNPs on prostate cancer (PCa) cell line PC3 with the aim of demonstrating that the interaction between UV-light and mTiNPs positively impacts the nanomaterial’s cytotoxic efficiency. Moreover, we assessed the differential expression of key oncomiRs and tumor suppressor (TS) miRNAs, as well as their associated target genes, in cells undergoing this treatment. Methods: PBS-suspended mTiNPs exposed to 290 nm UV light were added at different concentrations to PC3 cells. Cell viability was determined after 24 h with a crystal violet assay. Then, the obtained IC50 concentration of UV-nanomaterial was applied to a new PC3 cell culture, and the expression of a set of miRNAs and selected target genes was evaluated via qRT-PCR. Results: The cells exposed to photo-activated mTiNPs required 4.38 times less concentration of the nanomaterial than the group exposed to non-irradiated mTiNPs to achieve the half-maximal inhibition, demonstrating an improved cytotoxic performance of the UV-irradiated mTiNPs. Moreover, the expression of miR-18a-5p, miR-21-5p, and miR-221-5p was downregulated after the application of UV-mTiNPs, while TS miR-200a-5p and miR-200b-5p displayed an upregulated expression. Among the miRNA target genes, PTEN was found to be upregulated after the treatment, while BCL-2 and TP53 were underexpressed. Conclusions: Our cytotoxic outcomes coincided with previous reports performed in other cancer cell lines, strongly suggesting UV-irradiated mTiNPs as a promising nano-therapeutic approach against PCa. On the other hand, to the best of our knowledge, this is the first report exploring the impact of UV-irradiated mTiNPs on key onco- and TS microRNAs in PCa cells.

Suppression of dopamine receptor 2 inhibits the formation of human prostate cancer PC‑3‑derived cancer stem cell‑like cells through AMPK inhibition.

Cancer stem cells (CSCs) contribute to the resistance of intractable prostate cancer, and dopamine receptor (DR)D2 antagonists exhibit anticancer activity against prostate cancer and CSCs. Human prostate cancer PC-3 cells were used to generate CSC-like cells, serving as a surrogate system to identify the specific DR subtype the inhibition of which significantly affects prostate-derived CSCs. Additionally, the present study aimed to determine the downstream signaling molecules of this DR subtype that exert more profound effects compared with other DR subtypes. The inhibitory effects of specific antagonists or small interfering (si)RNAs on DR subtypes were compared by analyzing morphological changes of cells, expression patterns of pluripotency markers, cell growth inhibitory activities and in vitro cell invasion. L-741,626, a specific DRD2 antagonist, induced morphological changes in PC-3-derived CSC-like cells, suppressed the expression of Oct4 (a pluripotency marker), and inhibited the growth of cells and tumors. The proliferation of heterozygous null PC-3 cells, generated using the CRISPR/Cas9 method, was slow, and their sphere-forming ability was substantially reduced, indicating a diminished capacity to produce CSCs. In addition, the phosphorylation of AMPK was suppressed by DRD2 siRNA and the heterozygous knockout of DRD2 in PC-3 cells, indicating that AMPK may be a putative downstream signaling molecule involved in the production and maintenance of PC-3-derived CSC-like cells. Specific inhibition or suppression of DRD2 caused PC-3-derived CSC-like cells to lose their properties and inhibited the formation of PC-3-derived CSC-like cells, followed by inhibition of the phosphorylation of AMPK, which is considered a putative downstream signaling molecule of DRD2. Further understanding of the mechanisms by which DRD2 regulates AMPK and the effects of AMPK inhibition on the properties of PC-3-derived CSC-like cells may provide valuable insights into the identification of molecular targets for treating intractable prostate cancer wherein AMPK is constitutively activated.

Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ

BackgroundPoly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi.Results[carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection.ConclusionsAlthough [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated.

Lactoferrin conjugated radicicol nanoparticles enhanced drug delivery and cytotoxicity in prostate cancer cells.

Pyruvate dehydrogenase kinase-1 (PDK1) plays a crucial role in cancer cell metabolism by regulating the glycolytic pathway. Although, inhibitors targeting PDK1 have been effective in inhibiting glycolysis in multiple cancers, their lack of selectivity leading to off-target effects limit their therapeutic benefit. Herein, we investigated the inhibitory potential of six PDK1 inhibitors on cellular proliferation, migration, and invasion of androgen-sensitive LNCaP and androgen-negative PC-3 prostate cancer cells. Of the six PDK1 inhibitors, radicicol and dicumarol significantly inhibited cellular proliferation and exhibited lower metabolic activity in both LNCaP and PC-3 metastatic prostate cancer cells. Radicicol was highly effective at lower concentration. Moreover, radicicol significantly inhibited migration and invasion in PC-3 cells. We then developed a lactoferrin nanoparticle (LF-NP) encapsulated with Radicicol (Ra-LF-NP), using a rotary evaporation method. Spheroid assays confirmed the higher inhibitory potential of Ra-LF-NP with a reduction in spheroid area by 80%, and invasiveness compared to radicicol alone. Lactoferrin receptors are overexpressed on the surface of many cancer cells, including prostate cancer. Conjugating radicicol with lactoferrin nanoparticles, potentially enhanced the specific uptake of the drug by prostate cancer cells while minimizing the off-target effects on healthy cells. This targeted therapy approach could lead to improved treatment outcomes and reduced side effects. Our study demonstrated the potential of radicicol delivery by lactoferrin-conjugated nanoparticle as an efficient drug delivery strategy for prostate cancer treatment.

Comparative Analysis of Acquired Resistance to Bortezomib in Prostate Cancer Cells Using Proteomic and Bioinformatic Tools.

Chemotherapy is a potent tool against cancer, but drug resistance remains a major obstacle. To combat this, understanding the molecular mechanisms behind resistance in cancer cells and the protein expression changes driving these mechanisms is crucial. Targeting the Ubiquitin-Proteasome System (UPS) has proven effective in treating multiple myeloma and shows promise for solid tumours. Despite initial success with the proteasome inhibitor bortezomib, acquired resistance soon after treatment poses a significant challenge to its efficacy. In this study, we explored proteins potentially involved in acquired resistance to bortezomib using label-free nLC-MS/MS proteomic analysis. The investigation revealed 299 proteins with notable differences in expression levels in the bortezomib-resistant PC3 prostate cancer cell line. Using bioinformatics tools, we illustrated the top 10 gene ontology (GO) processes [e.g., translational initiation (p = 5.964E-10), CRD-mediated mRNA stabilisation (p = 1.636E-5), and hydrogen ion transmembrane transport (p = 6.46E-5)] and the top 20 KEGG [e.g., metabolic pathways (p = 7.601E-13), biosynthesis of amino acids (p = 3.834E-12), and chemical carcinogenesis-reactive oxygen species (p = 1.891E-4)] and REACTOME [e.g., metabolism (p = 4.182E-21), translation (p = 9.484E-18), and Nonsense-Mediated Decay (NMD) (p = 1.829E-8)] pathways in the PC3-resistant cells. We further refined our results by comparing them with globally validated TCGA datasets. We correlated the 299 proteins identified through proteomic analysis with tumour aggressiveness and resistance by comparing them with the TCGA nodal metastasis N0 vs. N1 datasets using the UALCAN portal and identified 37 proteins consistent with our results. We believe that a combination of bortezomib with chemotherapeutics targeting these proteins could be effective in overcoming the resistance developed against bortezomib.

Filicinic Acid-Based Meroterpenoids with Antiproliferative Activity against Prostate Cancer PC-3 Cells from Dryopteris wallichiana.

Nine new structurally diverse filicinic acid-based meroterpenoids (1-9) with four kinds of carbon skeletons were isolated from the rhizomes of Dryopteris wallichiana. Their structures, including the absolute configurations, were elucidated by comprehensive analysis of spectroscopic data, quantum chemical calculations, and single-crystal X-ray diffraction. Structurally, compounds 1-4 feature an unprecedented 6/6/5/6/6/6 hexacyclic system with a rare oxaspiro[4.5]decane core linking the filicinic acid and ent-kaurane-type diterpene moieties. Compounds 5-6 are rare hybrids of filicinic acid and carotane-type sesquiterpene. Compound 7 is an unusual rearranged filicinic acid-carotane-type sesquiterpene meroterpenoid. Compounds 8-9 are two enantiomeric pairs of new meroterpenoids constructed by filicinic acid and a germarane-type sesquiterpene. A plausible biosynthetic pathway for the nine compounds was proposed. Notably, compounds 5, 6, (+)/(-)-8, and (+)/(-)-9 were discovered to possess antiproliferative activity against PC-3 cells based on virtual screening, and in vitro bioassay. An interactive preprint version of the article can be found at https://www.authorea.com/doi/full/10.22541/au.172666991.17272585/v1.

The Activation of the CCND1 Promoter by AP-1 and SOX Transcription Factors in PC3 Prostate Cancer Cells Can Be Prevented by Anacardic Acid Analogs.

Targeting more than one in nine men before age 70, prostate cancer is the most common type of cancer in men. The increased levels of cyclins, leading to activation of cyclin-dependent kinases (CDKs), play a critical role in the increased proliferation of prostate cancer cells. In this study, the regulation of the cyclin D1 (CCND1) promoter activity by activator protein-1 (AP-1) and SRY-related HMG-box (SOX) transcription factors has been characterized in PC3 prostate cancer cells. The SOX and AP-1 transcription factors can cooperate to activate the CCND1 promoter in PC3 prostate cancer cells and such cooperation can be enhanced by protein kinase A (PKA) and/or mitogen-activated protein kinase kinase 1 (ERK kinase 1, MAP2K1) signaling pathways. Moreover, anacardic acid analogs have been assessed for their potential in reducing cell viability and CCND1 promoter activity. The anacardic acid analog 8b, obtained from γ-resorcylic acid, reduces the viability and proliferation of PC3 cells by decreasing CCND1 promoter activity. The effect of analog 8b, which perfectly mimics the structure of anacardic acid, can be attributed to the inhibition of the activities of the transcription factors SOX and AP-1, which are important regulators of CCND1 promoter activity in prostate cancer cells.

Modification of Fc-fusion protein structures to enhance efficacy of cancer vaccine in plant expression system.

Epithelial cell adhesion molecule (EpCAM) fused to IgG, IgA and IgM Fc domains was expressed to create IgG, IgA and IgM-like structures as anti-cancer vaccines in Nicotiana tabacum. High-mannose glycan structures were generated by adding a C-terminal endoplasmic reticulum (ER) retention motif (KDEL) to the Fc domain (FcK) to produce EpCAM-Fc and EpCAM-FcK proteins in transgenic plants via Agrobacterium-mediated transformation. Cross-fertilization of EpCAM-Fc (FcK) transgenic plants with Joining chain (J-chain, J and JK) transgenic plants led to stable expression of large quaternary EpCAM-IgA Fc (EpCAM-A) and IgM-like (EpCAM-M) proteins. Immunoblotting, SDS-PAGE and ELISA analyses demonstrated that proteins with KDEL had higher expression levels and binding activity to anti-EpCAM IgGs. IgM showed the strongest binding among the fusion proteins, followed by IgA and IgG. Sera from BALB/c mice immunized with these vaccines produced anti-EpCAM IgGs. Flow cytometry indicated that the EpCAM-Fc fusion proteins significantly activated CD8+ cytotoxic Tcells, CD4+ helper Tcells and B cells, particularly with EpCAM-FcKP and EpCAM-FcP (FcKP) × JP (JKP). The induced anti-EpCAM IgGs captured human prostate cancer PC-3 and colorectal cancer SW620 cells. Sera from immunized mice inhibited cancer cell proliferation, migration and invasion; down-regulated proliferation markers (PCNA, Ki-67) and epithelial-mesenchymal transition markers (Vimentin); and up-regulated E-cadherin. These findings suggest that N. tabacum can produce effective vaccine candidates to induce anti-cancer immune responses.

Novel NO Pincer Type 2‐(5,6‐Dichlorobenzo[d]thiazol‐2‐yl)phenol and Its Complex of Pt (II): Synthesis, Spectral Characterization, DFT Calculations, Cell Cycle Arrest, Apoptosis Assay, Cytotoxicity, DNA Binding, and Biological Evaluation Study

ABSTRACTA new novel NO pincer type bezo[d]thiazole ligand, 2‐(5,6‐dichlorobenzo[d]thiazol‐2‐yl)phenol (HDCBTP) is synthesized through reacting 2‐amino‐4,5‐dichlorobenzenethiol and 2‐hydroxybenzoic acid in 1:1 ratio. Nano‐sized bivalent Pt (II) complex is created and subsequently characterized using various physical methods. The complex structural geometry is validated by employing the density functional theory (DFT) approach, utilizing DMOL3 determinations. Based on the elemental analysis results, the complexes are inferred to follow the overall formula [Pt (DCBTP)2]. Quantum chemical calculations, along with electronic spectra findings, indicate that Pt (II) complex exhibits a square planar configuration. The XRD, EDX, TEM, and AFM analyses of the studied complex unveil distinct and strong diffraction peaks, indicating its crystalline nature and providing evidence of its nano‐sized particle sizes. Viscosity measurements and absorption titration techniques were used to study the interaction between Pt (II) complex and CT‐DNA. The results showed that the complexes were bound to CT‐DNA via a typical intercalation binding mode. The in vitro antimicrobial efficacy of HDCBTP and its Pt (II) complex was inspected against various bacterial and fungal pathogens. The results highlight these compounds as a highly effective fungicides and bactericides. In vitro cytotoxic effects of the formulated complex were explored utilizing PC3 prostate cancer cell lines. According to IC50 and selective index (SI) measurements, it was shown that the complex exhibited higher potency against HePG2 cell lines. Moreover, Pt (II) complex exhibited the capability for triggering DNA damage in HePG2 cells, resulting in dose‐dependent cell apoptosis. Subsequent investigations revealed that complex triggered cell cycle arrest during the S and G2 phases.

Biosynthesis of novel MnO<SUB>2</SUB> nanocapsules via <I>C. spinosa</I> extract and honeybee-derived chitosan: exploring antibacterial and anticancer properties

This investigation delves into the integration of Capparis spinosa extract (CSLe) onto manganese dioxide nanoparticles (MnO2NPs) and chitosan derived from honeybees (CSH) in a nanostructured configuration. The resultant nanocomposites, namely CSLe@MnO2NPs and CSH/CSLe@MnO2NPs, underwent thorough characterization through various analytical techniques. UV-Vis spectroscopy unveiled distinctive features, such as ligand-to-metal charge transfer and photoluminescence, affirming the successful chitosan-functionalization of the MnO2NPs, thereby differentiating them from their pristine counterparts. FTIR spectra corroborated the binding of chitosan and identified crucial molecular functional groups. SEM-EDX analysis revealed the morphological properties, addressing non-uniform sizes in the as-calcined MnO2NPs by the uniform coating of CSH on CSLe@MnO2NPs, while EDX confirmed the presence of essential elements. TEM and SAED provided insights into the spherical morphology, crystalline structure, and lattice planes of these nanoparticles. Size distribution measurements highlighted distinctions between CSLe@MnO2NPs and CSH/CSLe@MnO2NPs. The nanomaterials underwent evaluation for their antimicrobial properties against a spectrum of Gram-negative and Gram-positive bacterial strains, with CSH/CSLe@MnO2NPs exhibiting the highest bactericidal activity. Additionally, they demonstrated low minimum inhibitory concentration (MIC) values, especially against S. aureus (MIC as low as 12.5 µg/ml). Their efficacy extended to anti-biofilm formation, significantly diminishing biofilm development in a dose-dependent manner, a pivotal factor in addressing biofilm-related infections. The study also scrutinized their cytotoxicity against normal Vero and PC3 prostate cancer cells, revealing potential anticancer properties. Dose-dependent reductions in cell viability were observed for both normal and cancer cells. In conclusion, these findings underscore the versatility and promise of CSH/CSLe@MnO2NPs in diverse biomedical applications, including antibacterial, anti-biofilm, and anticancer therapies.

Antiproliferative Activity and Molecular Docking Analyses of Sesquiterpene Lactones Obtained from Activity-Directed Isolation of Centaurea saligna (K.Koch) Wagenitzin Neoplastic Cells.

Secondary metabolites obtained from plants are among the most commonly encountered chemotherapeutics used in cancer treatment. Plants contain thousands of metabolites; therefore, it is important to reach the compound primarily responsible for activity by fractionating plant extracts through activity-guided isolation. The cytotoxic activities of C. saligna fractions, sub-fractions, and all pure compounds obtained from the plant were investigated in vitro using MCF-7 (human breast cancer), HeLa (human cervical cancer), and PC-3 (prostate cancer) cell lines. Eighteen compounds were isolated from C. saligna, comprising eight sesquiterpene lactones, three flavonoids, five lignans, and two phenolic compounds, with their structures elucidated through 1H-NMR, 13C-NMR, and HMBC spectroscopic techniques. The molecular docking scores of the pure compounds obtained from these sub-fractions were determined using both AutoDock and AutoDock Vina programs. It has been proven that the affinities of linichlorin B and aguerin B for Bcl-2 are higher than those of other compounds, considering the calculated Ki values and placement scores. Notable activities of linichlorin B, cynaropicrin, and aguerin B (with IC50 values of 13.67μg/ml, 6.79μg/ml, and 3.46μg/ml, respectively) were detected in the PC-3 cell line; aguerin B demonstrated activity most comparable to the standard anticancer agent doxorubicin. Likewise, linichlorin B, aguerin B, and cynaropicrin demonstrated notable efficacy in the HeLa and MCF-7 cell lines, as reported by the American National Cancer Institute. Aguerin B, linichlorin B, and cynaropicrin are projected to serve as promising novel chemotherapeutic agents for cancer therapy.

BUD23 promote the cell proliferation ability by affecting the PPAR signaling pathways: evidence from the online dataset and cell experiment

IntroductionProstate cancer is a major public health challenge for men worldwide, being the second most common cancer diagnosis and the fifth leading cause of cancer-related deaths among men. The etiology of prostate cancer is multifactorial, with age, genetic predispositions, and lifestyle factors playing critical roles. The role of the peroxisome proliferator-activated receptors (PPARs) in prostate cancer remains complex and not fully elucidated.MethodsTranscriptomic data from The Cancer Genome Atlas (TCGA) were utilized for this study. The data were analyzed using single-sample Gene Set Enrichment Analysis (ssGSEA), Gene Ontology (GO) enrichment analysis, KEGG pathway analysis, and Gene Set Enrichment Analysis (GSEA). A prognosis-prediction model was constructed using Cox regression and LASSO analysis. Functional experiments, including Western blotting, quantitative PCR (qPCR), Cell Counting Kit-8 (CCK-8) assays, and EdU incorporation assays, were performed to validate the role of BUD23 in prostate cancer.ResultsSignificant differences were observed in the immune microenvironment and HLA gene expression profiles between high and low PPAR expression groups in prostate cancer. The high PPAR group exhibited a less active immune microenvironment with higher fractions of immunosuppressive T regulatory cells (Tregs). A robust prognostic model identified key genes, including BUD23, associated with patient survival. Elevated BUD23 expression was correlated with more aggressive clinical features such as advanced pathological stages, nodal metastasis, and higher Gleason scores. Knockdown of BUD23 in PC-3 and LNCaP prostate cancer cell lines significantly inhibited cell proliferation. Western blotting and qPCR confirmed effective BUD23 knockdown, and CCK-8 and EdU assays demonstrated reduced cell proliferation. BUD23 knockdown resulted in significant reductions in PPAR-α, PPAR-β, and PPAR-γ protein levels, suggesting a regulatory axis between BUD23 and PPARs in prostate cancer.ConclusionThe study highlights the distinct roles of PPARα, PPARβ/δ, and PPARγ in prostate cancer progression and their potential as therapeutic targets. Elevated BUD23 expression is associated with aggressive prostate cancer features and patient survival, making it a potential prognostic biomarker. The knockdown of BUD23 not only inhibited cell proliferation but also reduced the expression of PPAR-related proteins, indicating a potential regulatory axis between BUD23 and PPARs. These findings suggest that targeting BUD23 could modulate PPAR signaling and inhibit tumor growth in prostate cancer.

Effects of decursinol angelate on viability and apoptosis in PC-3 prostate cancer cells: In vitro study.

Prostate cancer represents the predominant malignant neoplasm observed in the male population and ranks second in terms of mortality attributable to malignant neoplasm among men. Decursinol angelate (DA), derived from the plant Angelica gigas Nakai (AGN), has demonstrated anti-cancer effectiveness through the induction of intrinsic and extrinsic apoptosis pathways, inhibition of cancer cell proliferation, having anti- neovascularization, anti-inflammatory anti-oxidative activities and stimulating the immune process. The aim of this study was to determine the IC50 dose of DA on human prostate cancer cell line PC-3, as well as to assess its effects on cell viability and apoptosis. PC-3 cells were utilized in this study due to its hormonal therapy resistance characteristics. The treatment commenced with the determination of the IC50 of DA and cell viability using the CCK-8 method as a baseline dose. A combination with abiraterone acetate (AA) was performed using an escalated dose based on its IC50 to identify whether DA has a synergy with AA in decreasing PC-3 cell viability. Apoptosis levels were measured using flow cytometry. The research includes a control group (C) and three treatment groups: AA group, DA group, and DA+AA group. GraphPad Prism, SPSS version 25 and CompuSyn software were used for statistical analysis. This study reveals that the IC50 dose of DA is 13.63 µM. The decrease of PC-3 cell viability exposed to DA occurs in a dose-dependent manner. Additionally, PC-3 cell apoptosis is significantly increased in both the DA group and DA+AA compared to the control. Moreover, no difference in apoptosis level is noted between the DA and AA groups. Notably, there is a synergy between DA and AA, where a specific dose equal to one-fourth of the IC50 dose results in greater efficacy in reducing PC- 3 cell viability compared to individual treatments of either DA or AA at the IC50 doses. This study demonstrates the potential of decursinol angelate as a single drug or combined with abiraterone acetate to reduce viability and increase apoptosis of castrate-resistant prostate cancer cells.

Glucose Upregulates ChREBP via Phosphorylation of AKT and AMPK to Modulate MALT1 and WISP1 Expression.

Glucose can activate the carbohydrate response element binding protein (ChREBP) transcription factor to control gene expressions in the metabolic pathways. The way of ChREBP involvement in human prostate cancer development remains undetermined. This study examined the interactions between prostate fibroblasts and cancer cells under the influences of ChREBP. Results showed that high glucose (30 mM) increased the phosphorylation of AKT at S473 and AMP-activated protein kinase (AMPK) at S485 in human prostate fibroblast (HPrF) cells and prostate cancer PC-3 cells. High glucose enhanced the expression of ChREBP, which increased the expressions of fibronectin, alpha-smooth muscle actin (α-SMA), and WNT1 inducible signaling pathway protein 1 (WISP1), magnifying the cell growth and contraction in HPrF cells in vitro. The cell proliferation, invasion, and tumor growth in prostate cancer PC-3 cells were enhanced by inducing the expressions of ChREBP, mucosa-associated lymphoid tissue 1 (MALT1), and epithelial-mesenchymal transition markers with high glucose treatment. Moreover, ectopic ChREBP overexpression induced NF-κB signaling activities via upregulating MALT1 expression in PC-3 cells. Our findings illustrated that ChREBP is an oncogene in the human prostate. High glucose condition induces a glucose/ChREBP/MALT1/NF-κB axis which links the glucose metabolism to the NF-κB activation in prostate cancer cells, and a glucose/ChREBP/WISP1 axis mediating autocrine and paracrine signaling between fibroblasts and cancer cells to promote cell migration, contraction, growth, and invasion of the human prostate.

Novel 4-((3-fluorobenzyl)oxy)benzohydrazide derivatives as promising anti-prostate cancer agents: Synthesis, characterization and in vitro & in silico biological activity studies

In this study, ten novel halogenated arylidenehydrazide derivatives were synthesized and characterized through ¹H, ¹³C APT, ¹⁹F NMR, HSQC, HMBC, HRMS, and FT-IR techniques. Cytotoxic evaluations against PC3 prostate cancer and HUVEC cell lines identified compounds 8 and 14 as lead candidates, achieving IC₅₀ values of 4.49 µM and 4.78 µM, respectively, with notable selectivity indexes of 12.15 and 11.78, underscoring their specificity against PC3 cells. Molecular docking studies targeting AR, VEGFR1, EGFR, and VEGFR2 suggested potential inhibitory mechanisms, with compounds 8 and 14 displaying substantial binding affinities for AR and VEGFR1. Compound 8 achieved IFD scores of -12.900 kcal/mol for AR and -10.895 kcal/mol for VEGFR1, while compound 14 recorded scores of -10.323 kcal/mol and -10.379 kcal/mol, respectively. Complementary MM-GBSA analyses revealed favorable binding energies, with compound 8 yielding ΔG values of -76.60 kcal/mol (AR) and -78.08 kcal/mol (VEGFR1) and compound 14 showing -80.67 kcal/mol (AR) and -78.61 kcal/mol (VEGFR1). MD simulations confirmed complex stability over 50 ns, indicating that compound 14 exhibited enhanced binding stability with key residues in AR and VEGFR1. ADME predictions highlighted drug-like properties, particularly for compounds 8 and 14, with high lipophilicity and favorable absorption characteristics, despite low aqueous solubility. SAR analysis emphasized the beneficial impact of halogen substitutions on potency and selectivity, establishing compounds 8 and 14 as promising candidates for further therapeutic development.

Multifunctional lanthanum oxide-doped carboxymethyl cellulose nanocomposites: A promising approach for antimicrobial and targeted anticancer applications

This study presents the synthesis and characterization of lanthanum oxide (La₂O₃)-doped carboxymethyl cellulose (CMC) nanocomposites via a solution casting method, designed to offer an eco-friendly, multifunctional material with significant potential in biomedical applications. Structural analysis using FTIR, XRD, and EDX confirmed successful La₂O₃ integration, with FTIR spectra indicating a distinctive LaO stretching peak at 628.2 cm−1, XRD patterns revealing enhanced crystallinity with notable peaks at 16.6°, 27.6°, and 49.8°, and EDX showing a uniform lanthanum distribution with a 10.41 mass% concentration. These enhancements in structural stability and crystalline properties underscore the composite's functional robustness. Biological assessments revealed the composite's substantial antimicrobial efficacy, demonstrating inhibition zones up to 31 mm against pathogenic strains such as E. coli, S. aureus, E. faecalis, K. pneumoniae, and C. albicans at a 15 wt% La₂O₃ concentration—surpassing conventional antimicrobial agents. Minimum inhibitory concentration (MIC) tests supported these findings, showing MIC values as low as 7.82 μg/mL, further validating the composite's heightened antimicrobial potency compared to pure CMC. In vitro cytotoxicity assays indicated selective anticancer effects of the La₂O₃/CMC nanocomposites, with IC₅₀ values of 327.7 μg/mL and 189.8 μg/mL against PC-3 prostate and A549 lung cancer cells, respectively. Remarkably, the composite showed minimal impact on normal lung fibroblasts (Wi-38), with an IC₅₀ value of 956.8 μg/mL, emphasizing its selectivity towards cancer cells. Collectively, these results highlight the La₂O₃/CMC composite as a biocompatible and multifunctional material suitable for both antimicrobial and targeted anticancer applications, aligning with the growing demand for safe, effective biomedical solutions.

Cellular targets of cytotoxic copper phenanthroline complexes: a multimodal imaging quantitative approach in single PC3 cells.

Metal complexes are emerging as promising alternatives to traditional platinum-based cancer treatments, offering reduced side effects. However, understanding their cellular uptake and distribution and quantifying their presence at the single cell level remains challenging. Advanced imaging techniques, including transmission electron microscopy, synchrotron radiation X-ray fluorescence, and energetic ion beam-based nuclear microscopy (scanning transmission ion microscopy, particle-induced X-ray emission, elastic backscattering spectrometry), allow detailed high-resolution visualization of structure and morphology, high sensitivity for elemental detection with quantification within single cells, and the construction of 3D models of metal distribution, positioning them as powerful tools for assessing the cellular uptake and compartmentalization of complexes. Three Cu(II) complexes [Cu(phen)2(H2O)](NO3)2 (1), [Cu(Me2phen)2(NO3)]NO3 (2) and [Cu(amphen)2(H2O)](NO3)2 (3), (phen = 1,10-phenanthroline, Me2phen = 4,7-dimethyl-1,10-phen, amphen = 5-amino-phen) were investigated for Cu uptake and distribution in PC3 prostate cancer cells. All complexes show significant Cu uptake regardless of media concentration. Cu concentrations in the cytoplasm and nucleus are similar between treatments. Complexes 1 and 3 concentrate Cu in the nuclear region and show a vesicle-like pattern around the nucleus, while 2 shows a dispersed cytoplasmic pattern with large vesicles. The 3D models confirm that Cu is not retained at the plasma membrane, with complex 1 targeting the nucleus and 2 remaining in the cytoplasm. These results highlight the importance of quantifying metal distribution and correlating it with structural changes to understand the relevance of the ligand in the mechanisms of cellular uptake and targeting, crucial for the development of effective metal-based cancer therapies.

Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2

Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC50 value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.

Talaketides A−G, linear polyketides with prostate cancer cytotoxic activity from the mangrove sediment-derived fungus Talaromyces sp. SCSIO 41027

Seven novel linear polyketides, talaketides A−G (1−7), were isolated from the rice media cultures of the mangrove sediment-derived fungus Talaromyces sp. SCSIO 41027. Among these, talaketides A−E (1−5) represented unprecedented unsaturated linear polyketides with an epoxy ring structure. The structures, including absolute configurations of these compounds, were elucidated through detailed analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HR-MS) data, as well as electronic custom distributors (ECD) calculations. In the cytotoxicity screening against prostate cancer cell lines, talaketide E (5) demonstrated a dose-dependent inhibitory effect on prostate cancer PC-3 cell lines, with an IC50 value of 14.44 μmol·L−1 . Moreover, compound 5 significantly inhibited the cloning formation of PC-3 cell lines and arrested the cell cycle in S-phase, ultimately inducing apoptosis. These findings indicate that compound 5 may serve as a promising lead compound for the development of a potential treatment for prostate cancer.