Prostate Cancer Cells Research Articles

The olfactory receptor OR51E2 regulates prostate cancer aggressiveness and modulates STAT3 in prostate cancer cells and in xenograft tumors

BackgroundDespite advancements in the detection and treatment of prostate cancer, the molecular mechanisms underlying its progression remain unclear. This study aimed to investigate the role of the receptor OR51E2, which is commonly upregulated in prostate cancer, in the progression of this disease.MethodsWe investigated the physiological effects of OR51E2 through CRISPR-Cas9-induced monoclonal OR51E2 knockout. We assessed in vitro and in vivo tumorigenicity and conducted transcriptomic and proteomic analyses of xenograft tumors derived from these knockout cells. Furthermore, we analyzed the effects of differences in OR51E2-expression levels in patients from a TCGA cohort.ResultsOR51E2-knockout cells exhibited increased proliferation, migration, adhesion, anchorage-independent colony formation, and tumor growth rates, resulting in a more aggressive cancer phenotype. Omics analyses revealed several potential pathways associated with significant molecular changes, notably an aberration in the STAT3 pathway linked to IL-6 signaling, highlighting a connection to inflammatory pathways. TCGA cohort analysis revealed that prostate cancer patients with low tumor OR51E2 expression had a worse prognosis and a higher average Gleason grade than those with higher expression levels. Additionally, this analysis supported the putative OR51E2-related modulation of the STAT3 pathway.ConclusionsOR51E2 is regulated throughout prostate cancer progression and actively influences cancer cell physiology affecting cancer aggressiveness. Reduced OR51E2 expression may adversely affect patient outcomes, potentially through alterations in the STAT3 pathway that impact cellular responses to inflammatory signaling.

The combination of poly(ADP-ribose) polymerase inhibitor and statin inhibits the proliferation of human castration-resistant and taxane-resistant prostate cancer cells in vitro and in vivo

BackgroundOlaparib exhibits antitumor effects in castration-resistant prostate cancer patients with germline mutations in DNA repair genes. We previously reported that simvastatin reduced the expression of DNA repair genes in PC-3 cells. The efficacy of combination therapy using olaparib and simvastatin as “BRCAness” in castration-resistant and taxane-resistant prostate cancers was evaluated in this study.MethodsPC-3, LNCaP, and 22Rv1 human prostate cancer cell lines were used to develop androgen-independent LNCaP cells (LNCaP-LA). mRNA and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Cell viability was determined using the MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin with or without olaparib.ResultsThe mRNA levels of BRCA1, BRCA2, RAD51, FANCD2, FANCG, FANCA, BARD1, RFC3, RFC4, and RFC5, which are known DNA repair genes, were downregulated by simvastatin in androgen-independent prostate cancer cells, such as PC-3, LNCaP-LA, and 22Rv1 cells. In contrast, the expression of all these genes remained unchanged in androgen-dependent LNCaP cells following treatment with simvastatin. Furthermore, simvastatin increased the expression of above stated genes in normal prostate stromal cells (PrSC). The reduction in BRCA1 and BRCA2 expression following siRNA transfection increased the cytocidal effects of Olaparib in PC-3 and LNCaP-LA cells. The combination of olaparib and simvastatin further inhibited cell proliferation compared to monotherapy with either drug in PC-3, 22Rv1, and LNCaP-LA cells but not in PrSC cells. In a 22Rv1-derived mouse xenograft model, the combination of olaparib and simvastatin enhanced the inhibition of cell proliferation. Moreover, we established a 22Rv1 cell line with acquired resistance to Cabazitaxel (22Rv1-CR). In 22Rv1-CR cells, simvastatin also decreased the expression of BRCA1, BRCA2, and FANCA, and the combination of olaparib and simvastatin further enhanced the inhibition of cell proliferation compared with treatment with either of the drugs alone.ConclusionsSimvastatin altered the expression of several genes associated with DNA repair in castration-resistant and taxane-resistant prostate cancer cells. The combination of poly (ADP-ribose) polymerase inhibitors and drugs that decrease DNA repair gene expression can potentially affect castration-resistant and taxane-resistant prostate cancer growth.

PLGA/TPGS nanoparticles for docetaxel delivery: the pegylation effect on nanoparticle physicochemical properties and uptake and cytotoxicity in prostate cancer cells.

PLGA/TPGS nanoparticles for docetaxel delivery: the pegylation effect on nanoparticle physicochemical properties and uptake and cytotoxicity in prostate cancer cells.

E2F4 Promotes Malignant Behaviors of Prostate Cancer Through Activating MUC1 Expression Transcriptionally.

The malignant features of prostate cancer (PC) threaten the patient's life. MUC1 was observably enhanced in PC. However, the reason for higher MUC1 expression in PC is still unclear and deserves to be further investigated. The abundance of MUC1 and E2F4 was evaluated using RT-qPCR in PC patients and PC cells. Pearson correlation coefficient analyzed the relationship between E2F4 and MUC1 in tissues from PC patients. Malignant phenotypes were examined using clone formation, scratch tests, transwell, and flow cytometry. The JASPAR website, luciferase activity assay, and ChIP were employed for validating interplays between E2F4 and the MUC1 promoter. MUC1 and E2F4 were abnormally elevated in samples of PC patients and PC cells. MUC1 silencing resulted in suppression of growth and metastasis and promotion of cell apoptosis of PC cells. Additionally, E2F4 could provoke the transcriptional activity of MUC1 to enhance MUC1 expression. Furthermore, E2F4 knockdown inhibited malignant features of PC cells, which was abolished by MUC1 overexpression. Our findings revealed that E2F4 silencing led to the suppression of growth and metastasis and the promotion of cell apoptosis of PC cells through reducing MUC1 expression, which offered targeting molecules for PC treatment.

Elevated VRK1 levels after androgen deprivation therapy promote prostate cancer progression by upregulating YAP1 expression

PurposeVaccinia-related kinase 1 (VRK1) is a serine-threonine kinase involved in the proliferation and migration of various cancer cells. However, its role in prostate cancer (PCa), particularly in the development of therapeutic resistance, remains unclear.MethodsWe established an androgen-independent PCa cell line derived from LNCaP prostate cancer cells and conducted transcriptome and proteome sequencing together with bioinformatic analyses of large clinical sample databases to investigate the potential role of VRK1 in PCa progression. The correlation between VRK1 and androgen receptor (AR) signaling was evaluated under simulated clinical treatment conditions. The effects of VRK1 on cell proliferation were assessed in vitro and in vivo using Cell Counting Kit-8 and colony formation assays. Additionally, proteome and transcriptome sequencing, combined with rescue experiments were performed to explore VRK1-regulated signaling pathways related to cell proliferation and therapeutic resistance.ResultsVRK1 expression was elevated during the progression of androgen-dependent prostate cancer to castration-resistant prostate cancer under therapeutic conditions, and high VRK1 expression was associated with a poor prognosis in patients with PCa. VRK1 was regulated by AR signaling, and its silencing suppressed PCa cell proliferation both in vitro and in vivo. VRK1 drove cell proliferation and therapeutic resistance in PCa by modulating yes-associated protein 1 (YAP1).ConclusionsVRK1 serves as a prognostic marker in PCa, regulated by AR signaling. VRK1 depletion inhibited cell proliferation both in vitro and in vivo, while elevated VRK1 upregulated YAP1, promoting cell proliferation and therapeutic resistance.

Research on correlations of miR-374a-5p expression with progression and prognosis of prostate cancer

Prostate cancer (PCa) is a frequently occurring malignant tumor affecting male reproductive system. miR-374a-5p was identified to participate in regulation of several tumors. The aim of the research was to discuss the influence for miR-374a-5p upon PCa progression and prognosis. A total of 112 PCa and 110 benign prostatic hyperplasia tissue samples were collected for the study. Real-time quantitative polymerase chain reaction was adopted to examine miR-374a-5p level in PCa tissues and cells. Kaplan–Meier and Cox model were applied to evaluate prognostic significance of miR-374a-5p for PCa. CCK8 and Transwell assays were carried out to analyze the efficacy of miR-374a-5p in PCa cell proliferation, migration and invasion. miR-374a-5p was under-expressed in PCa tissues and cells. Low expression of miR-374a-5p is linked to less favorable prognosis in PCa sufferers. Additionally, Cox analysis revealed that miR-374a-5p and TNM stage were two independent prognostic factors for PCa. Cellular assays showed that upregulating miR-374a-5p suppressed PCa cell proliferation, migration, and invasion. Conversely, knockdown of miR-374a-5p facilitated PCa cell proliferation, migration, and invasion. miR-374a-5p expression decreased in PCa and was remarkably related to poor prognosis in PCa patients. miR-374a-5p acts in PCa by inhibiting cell proliferation, migration, and invasion. Consequently, miR-374a-5p has potential to act as a prognostic biomarker and a target for clinical therapeutic intervention in PCa.

Prostate cancer-specific proinflammatory cytokines and chemokines impact on cancer stem cell development, lineage plasticity and heterogeneity in an Ancestral/racially diverse population: review.

Since 1976, Surveillance Epidemiology End Results (SEER) began collecting ethnicity data for the National Cancer Institute. The incidence of prostate cancer (PCa) among African American men (AAM) has been 60-70% higher than any other ethnicity and mortality rate 2 to 3 times greater than European American men (EAM), and those data have not changed. We reported in 2010 that PCa grows faster among AAM compared to EAM. In 2013, we utilized bioinformatics and ingenuity gene network analysis and in silico analysis to identify driver genes responsible for "racial" disparity. Genes associated with lipid metabolism were more expressed among EAM and genes associated with inflammation were more expressed among AAM. In 2021, we unraveled the network of the Ingenuity gene analysis and reported that the inflammatory genes, specifically proinflammatory cytokines and chemokines initiated multiple pathways. A literature review of these pathways showed that they induce castrate-resistant PCa (CRPC), metastasis, oxidative stress, DNA damage, cancer stem cells, lineage plasticity, and tumor heterogeneity. These genes and processes will be discussed in detail as to how they are initiated by proinflammatory cytokines and chemokines and how they act in a domino effect. Most importantly, how lineage plasticity changes the chemistry of the cancer stem cells of the original PCa so that it is no longer recognized by current therapy, chemotherapy, and immunotherapy. This suggests a paradigm change of current therapy is necessary to significantly reduce mortality of advanced PCa.

Modified Nucleosides as Potential Biomarkers of Prostate Cancer: Targeted Metabolomics of In Vitro Cell Samples by MEKC-UV.

Prostate cancer is the second most common cancer among men globally, with over 1.4 million new cases and nearly 400000 deaths reported in 2022. Despite the availability of diagnostic tools such as the Prostate Specific Antigen (PSA) test, its low sensitivity reinforces the need for the exploration of more reliable biomarkers. In this context, metabolomics offers a promising approach for identifying sensitive biomarkers to improve cancer diagnosis and treatment. Therefore, this study aimed to conduct a targeted metabolomic analysis of the extracellular environment of In Vitro non-tumoral and cancer prostate cells to compare the levels of eight nucleosides using micellar electrokinetic capillary chromatography with UV detection (MEKC-UV). The method was adapted from a previously optimized protocol for blood serum, with minor adjustments to meet the Brazilian National Health Surveillance Agency (ANVISA) standards. Nucleosides were extracted via solid-phase extraction (SPE), and cell cultures were maintained under controlled conditions at 37°C with 5% CO2 until reaching 80% confluence. The optimized MEKC-UV method demonstrated precision and accuracy, although the Youden test indicated some lack of robustness. Statistical analysis using a two-tailed t-test revealed significantly higher adenosine levels in non-tumoral cells, whereas uridine and 5-methyluridine concentrations were elevated in cancer cells. Inosine was detected exclusively in the non-tumoral cell line. Nevertheless, the method's innovative and cost-effective nature underscores its potential as a tool for cancer biomarker identification, with distinct nucleoside patterns in cancer cells offering valuable insights for disease recognition.

Wnt5a augments intracellular free cholesterol levels and promotes castration resistance in prostate cancer

BackgroundProstate cancer (PCa) is a leading cause of cancer-related mortality in men globally. While androgen deprivation therapy (ADT) can extend the asymptomatic phase and overall survival of patients with metastatic PCa, prolonged ADT often leads to the development of castration-resistant prostate cancer (CRPC) within 18–24 months. The mechanisms underlying CRPC remain incompletely understood, presenting a significant challenge in clinical prostate cancer treatment.MethodsIn this study, we investigated the role of Wnt5a, a member of the Wnt family, in CRPC. Tumor tissues from CRPC patients were analyzed to assess the expression levels of Wnt5a. Prostate cancer cells were used to examine the impact of Wnt5a on androgen-dependent and -independent growth, as well as sensitivity to bicalutamide. RNA-seq analysis, qRT-PCR, intracellular cholesterol content and the activation of the androgen receptor (AR) signaling pathway were evaluated to elucidate the mechanistic role of Wnt5a in CRPC progression. Drug target Mendelian randomization analysis was performed to investigate the effect of PCSK9 inhibitor on prostate cancer.ResultsOur study revealed a significant overexpression of Wnt5a in tissues from CRPC tumors. Wnt5a was found to enhance both androgen-dependent and -independent growth in prostate cancer cells while reducing their sensitivity to bicalutamide. Mechanistically, Wnt5a was shown to upregulate intracellular free cholesterol content and activate the AR signaling pathway, contributing to hormone therapy resistance in CRPC. PCSK9 inhibitor significantly reduced the risk of PCa.ConclusionsThe findings of this study highlight a novel molecular mechanism underlying endocrine therapy resistance in CRPC mediated by Wnt5a. Targeting Wnt5a or reducing cholesterol level would be a promising therapeutic strategy for the treatment of CRPC, providing new insights into potential avenues for combating this challenging form of prostate cancer.

Differential Effects of the Prolyl-Hydroxylase Inhibitor on the Cellular Response to Radiation

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response of cancer cells has not been determined. Hypoxic pretreatment increased the radiation sensitivity of A549 lung adenocarcinoma cells, whereas hypoxic culture after irradiation decreased the radiation sensitivity of HSC2 oral squamous cell carcinoma cells. Treatment of PC9 lung adenocarcinoma and HSC2 cells with the PHI FG-4592 significantly increased radiation resistance, whereas A549 and TIG3 lung fibroblast cells tended to be sensitized, suggesting cell type-specific differential effects of PHI. Quantitative RT-PCR analyses revealed that the basal and radiation-inducible expressions of DEC2, BAX, and BCL2 may be related to PHI-mediated radiation responses. Knock-down experiments showed that silencing of DEC2 sensitized both A549 and PC9 cells under PHI-treated conditions. On the other hand, silencing of p53, which regulates BAX/BCL2, desensitized A549 cells expressing wild-type p53, but not PC9 cells, with mutant-type p53, to irradiation, regardless of whether PHI was treated or not. Taken together, PHI modifies radiation responses in a cell type-specific manner, possibly through DEC2 signaling.

Development of 2‐bis(quinolin‐2‐ylmethylene)hydrazine based half‐sandwich ruthenium(II) arene complexes with high cytotoxicity in castration‐resistant prostate cancer cells

Metal complexes that can target uncurable forms of cancer are in high demand. Presented herein is detailed characterization, anticancer activity and structure‐activity comparison for a set of Ru(II) arene chlorido organometallic complexes [(η6‐arene)(L)RuCl]PF6 (BzRuL and HmbRuL) using 2‐bis(quinolin‐2‐ylmethylene) hydrazine (L) as ligand. BzRuL and HmbRuL was characterized by elemental analyses, FTIR, 1H, 13C‐NMR, 1H‐1H COSY‐NMR, and ESI mass spectroscopy. Spectroscopic and single crystal XRD analysis suggested that the complexes BzRuL and HmbRuL exhibit a piano‐stool structure. These complexes exhibit potent anticancer activity (IC50 9.62 mM for BzRuL and 7.23 mM for HmbRuL) even more effective than the standard drug cisplatin in a castration‐resistant human prostatic adenocarcinoma cell line (PC‐3). Their comparative analysis with our recently reported highly active Ru(II) complex with same ligand pCYRuL (IC50 0.71 mM) is also presented. Both the complexes interact with dsDNA and likely induce apoptosis via DNA damage pathway. This study introduces a new family of Ru complexes with promising potential for preclinical development against incurable prostate cancer.

Erioflorin and Erioflorin Acetate Induce Cell Death in Advanced Prostate Cancer Through ROS Increase and NF-κB Inhibition

Germacranes are a type of sesquiterpene lactones with anti-inflammatory and cytotoxic properties against cancer cell lines. In this in vitro study, erioflorin and erioflorin acetate were isolated and purified from the leaves of Podanthus mitiqui Lindl (Mitique or Mitriu), a shrub endemic to Chile and traditionally used in Mapuche medicine to treat urinary and digestive disorders. Their effects on advanced prostate cancer cell lines (DU-145 and 22Rv1) were evaluated. Cytotoxicity was assessed using real-time cell death and clonogenic assays. Apoptosis was determined by measuring reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptotic cell percentage through flow cytometry. Gene expression of BAX and BCL-2 was analyzed via RT-qPCR, while NF-κB activation was studied in DU-145 cells and human monocytic NF-κB reporter assays using LPS stimulation and alkaline phosphatase activity quantification. Erioflorin acetate exhibited the highest cytotoxicity, with IC50 values of 35.1 µM (22Rv1) and 27.3 µM (DU-145), compared to erioflorin, which had IC50 values of 50.3 µM and 56.5 µM, respectively. Both compounds increased ROS levels, reduced ΔΨm, and induced apoptosis. RT-qPCR analysis revealed that erioflorin elevated the BAX/BCL-2 ratio, and both compounds inhibited NF-κB activation by preventing IκBα phosphorylation. In conclusion, the findings demonstrate that erioflorin and erioflorin acetate exert significant in vitro cytotoxic and cytostatic effects on prostate cancer cells, supporting their potential as natural candidates for prostate cancer therapy.

Exploring the roles of ncRNAs in prostate cancer via the PI3K/AKT/mTOR signaling pathway

Although various treatment options are available for prostate cancer (PCa), including androgen deprivation therapy (ADT) and chemotherapy, these approaches have not achieved the desired results clinically, especially in the treatment of advanced chemotherapy-resistant PCa. The PI3K/AKT/mTOR (PAM) signaling pathway is a classical pathway that is aberrantly activated in cancer cells and promotes the tumorigenesis, metastasis, resistance to castration therapy, chemoresistance, and recurrence of PCa. Noncoding RNAs (ncRNAs) are a class of RNAs that do not encode proteins. However, some ncRNAs have recently been shown to be differentially expressed in tumor tissues compared with noncancerous tissues and play important roles at the transcription and posttranscription levels. Among the types of ncRNAs, long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), and Piwi-interacting RNAs (piRNAs) can participate in the PAM pathway to regulate PCa growth, metastasis, angiogenesis, and tumor stemness. Therefore, ncRNA therapy that targets the PAM signaling pathway is expected to be a novel and effective approach for treating PCa. In this paper, we summarize the types of ncRNAs that are associated with the PAM pathway in PCa cells as well as the functions and clinical roles of these ncRNAs in PCa. We hope to provide novel and effective strategies for the clinical diagnosis and treatment of PCa.

C1QBP Promotes Prostate Cancer Progression and Lipid Accumulation by Negatively Regulating ALDH9A1.

Prostate cancer (PCa) relies heavily on lipid metabolism for energy acquisition, and lipid metabolic reprogramming plays a crucial role in its progression. Here, we utilized publicly available PCa databases and immunohistochemistry to evaluate C1QBP expression in PCa. We found that C1QBP is highly expressed in PCa, potentially due to promoter hypomethylation. Functional assays showed that C1QBP promotes cell proliferation, migration, and lipid accumulation in PCa cells. We identified differentially expressed proteins associated with C1QBP by using liquid chromatography-tandem mass spectrometry. Functional enrichment analysis revealed that C1QBP affects lipid metabolism and negatively regulates the lipid metabolism-related molecule ALDH9A1. Furthermore, ALDH9A1 intervention rescued the tumor suppression and lipid reduction caused by C1QBP knockdown. RNA sequencing (RNA-seq) was performed to explore C1QBP regulatory pathways at the mRNA level, revealing that C1QBP also affects the MAPK and p53 pathways, as well as the expression of lipid metabolism-related molecules. In conclusion, these findings suggest that C1QBP influences PCa progression and lipid deposition by regulating ALDH9A1, while other potential mechanisms may also be involved, indicating that C1QBP is a promising target for PCa treatment.

Intratumoral distribution and pharmacokinetics of the radiolabeled ICAM-1 targeting monoclonal antibody R6.5 in a prostate cancer mouse model.

Despite new therapies, castration-resistant prostate cancer (CRPC) is still incurable. Intercellular Adhesion Molecule 1 (ICAM-1) is a well-characterized cell surface protein involved in prostate cancer pathogenesis, differentially expressed during transition from hormone-sensitive to CRPC. This study aimed to investigate ICAM-1 as a target for imaging and radioimmunotherapy of CRPC.Anti-ICAM-1 antibody R6.5 was labeled with 111In or 177Lu, and a non-specific antibody with 177Lu. In vitro uptake of R6.5 was tested in PC-3 prostate cancer cells. Biodistribution studies, SPECT/CT imaging, and autoradiography were performed in a PC-3 xenograft model.In vitro uptake of R6.5 ([177Lu]Lu-R6.5) increased during 6 h of incubation. The uptake was higher at lower mAb concentration and could be blocked by 500 nM of unlabeled R6.5. In vivo and ex vivo biodistribution showed that [111In]In-R6.5 and [177Lu]Lu-R6.5 targeted the xenograft tumors better than the control Ab, however [111In]In-R6.5 had better tumor uptake than [177Lu]Lu-R6.5, probably due to less aggressive conjugation with chelator and smaller tumor sizes. From 24 h post-injection, the tumors in mice injected with [111In]In-R6.5 and [177Lu]Lu-R6.5 were visible on SPECT, optimal contrast at 48 h. Uptake was low in normal organs except the spleen and liver for all mAbs. Autoradiography showed [111In]In-R6.5 and [177Lu]Lu-R6.5 accumulated along the edges of viable tumor. The control Ab tended to accumulate in partly necrotic areas.This study demonstrates ICAM-1 as a potential target for theragnostics in CRPC.

Enhanced Retention of NTSR1-Targeted Radionuclide Therapeutics via Covalent Inhibitors in Pancreatic, Colorectal, and Prostate Cancer Models.

Neurotensin receptor subtype 1 (NTSR1) is overexpressed in numerous cancers. Our laboratory is exploring the utilization of covalent cysteine protease inhibitors (e.g., E-64) to increase tumor retention of targeted radionuclide therapeutics (TRTs) through protein adduct formation. Using this approach, we reported [177Lu]Lu-NA-ET1, an NTSR1-targeted construct. In this work, we continue the exploration of [177Lu]Lu-NA-ET1 in three different NTSR1-positive cancer models. [177Lu]Lu-3BP-227, a clinically investigated NTSR1-targeted construct, was utilized as a comparative benchmark. Both [177Lu]Lu-NA-ET1 and [177Lu]Lu-3BP-227 underwent in vitro investigation, including internalization and autoradiographic sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies, in NTSR1-positive AsPC-1, HT-29, and PC-3 cell lines. Biodistribution, human radiation dosimetry, and in vivo autoradiographic SDS-PAGE studies were performed by using the same models. A dose escalation study using 585 MBq (15.8 mCi) of [177Lu]Lu-NA-ET1 was implemented in immunocompetent CF-1 mice. In all three cell lines, [177Lu]Lu-NA-ET1 demonstrated similar cellular uptake profiles relative to those of [177Lu]Lu-3BP-227. Biodistribution studies of [177Lu]Lu-NA-ET1 revealed increased (1.9-4.4-fold) tumor retention and radiation dose delivery relative to the control. Analysis of the in vitro and in vivo cellular and tissue lysates showed protein adducts that ranged from approximately 25-35 kDa, consistent with cysteine cathepsins, the speculative protein binding partner. A total of 585 MBq (15.8 mCi) of [177Lu]Lu-NA-ET1 was administered and found to be well-tolerated. Incorporating the covalent inhibitor in [177Lu]Lu-NA-ET1 resulted in an improved retention and radiation dose delivery profile compared to [177Lu]Lu-3BP-227. Examination of the therapeutic potential of [177Lu]Lu-NA-ET1 and further exploration of the chemical biology of this approach is underway.

Silica-based EGFR-degrading nano-PROTACs for efficient therapy of non-small cell lung cancer.

Silica-based EGFR-degrading nano-PROTACs for efficient therapy of non-small cell lung cancer.

Antrodia cinnamomea Formula Suppresses Prostate Cancer Progression via Immune Modulation and PD-1/PD-L1 Pathway Inhibition

Prostate cancer remains a significant global health challenge, necessitating the development of novel therapeutic approaches. This study investigated the therapeutic potential of the Antrodia cinnamomea formula (XIANZHIFANG formula, XZF), comprising Antrodia cinnamomea, Sanghuangporus sanghuang, Ganoderma lucidum, Ganoderma sinense, and Inonotus obliquus, in prostate cancer treatment. HPLC analysis confirmed the presence of key triterpenoids, including Antcin A, B, C, K, and Zhankuic acid B, C, and 4,7-dimethoxy-5-methyl-1,3-benzodioxole. Cytotoxicity assays demonstrated that XZF (50–200 μg/mL) exhibited selective activity, maintaining viability in non-cancerous 293T-cells while enhancing the viability of activated CD8+ and CD4+ T-cells in a dose-dependent manner. XZF significantly reduced PD-1 expression in CD8+ T-cells but not in CD4+ T-cells and inhibited the PD-L1/PD-1 interaction, achieving 93% inhibition at 200 μg/mL. Furthermore, when combined with atezolizumab (1 μg/mL), XZF demonstrated complete blockade of PD-L1/PD-1 interaction. In prostate cancer cells, XZF exhibited differential antiproliferative effects. In PC-3 cells, XZF significantly reduced viability across a concentration range of 25–200 μg/mL, whereas DU145 cells showed only partial inhibition at higher concentrations (100–200 μg/mL). LNCaP cells exhibited a dose-dependent reduction in viability, mirroring the response pattern of PC-3 cells. Conditioned medium from XZF-treated macrophages, particularly human THP-1 cells, significantly suppressed the viability and migration of prostate cancer cells in a dose-dependent manner. Notably, the conditioned medium from XZF-treated THP-1 cells exhibited a stronger inhibitory effect on prostate cancer cell viability and migration compared to murine RAW 264.7 macrophages. These findings indicate that XZF exerts its therapeutic potential through multiple mechanisms, including direct antiproliferative effects on cancer cells, enhancement of T-cell responses, modulation of immune checkpoint pathways, and macrophage-mediated suppression of prostate cancer cell survival and migration. The pronounced effects observed in human macrophage models suggest a promising avenue for further investigation in clinical settings, particularly in combination with existing immunotherapies.

PSMA-Uptake Reveals Globet Cell Cancer of the Appendix in a Patient Staged for Prostate Cancer With PET/CT

18F-PSMA 1007 is an established tracer for staging intermediate and high-risk prostate cancer. Besides prostate cancer cells, benign tumors and inflammations/infections can show unspecific PSMA uptake. We present a case of incidental PSMA uptake of the appendix revealing a globet cell adenocarcinoma in histology after surgical resection. Globet cell tumors are rare neoplasms of the appendix. Patients with incidental PSMA uptake in the appendix should undergo further work-up.

L-asparaginase from the novel Fusarium falciforme AUMC 16563: extraction, purification, characterization, and cytotoxic effects on PC-3, HePG-2, HCT-116, and MCF-7 cell lines

BackgroundL-asparaginase has been a widely employed as antitumor enzyme for the treatment of acute lymphoblastic leukemia for almost three decades. The enzyme takes advantage of the inability of tumor cells to synthesize the L-asparagine and is killed by L‐asparagine deprivation. Despite the availability of bacterial sources for L-asparaginase, there is a growing interest in identifying new microbial sources with improved therapeutic properties. Therefore, this study aims to investigate the production of L-asparaginase from a fungal source, to explore its potential as a novel alternative enzyme for cancer treatment.ResultsFusarium falciforme AUMC 16563 was used to produce L-asparaginase (123.42 U/mL) after 5 days, 0.2% glucose and 1.0% asparagine; were used at 25 ˚C and pH 8.0. Employing two columns of chromatography (DEAE-cellulose and Sephacryl S 200 HR), the enzyme was purified 14.26-fold, reaching a maximum activity of 5109.4 U/mg. SDS-PAGE revealed a 46.06 kDa asparaginase. The Km and Vmax values for pure asparaginase using asparagine was 5.77 × 10− 2 mM and 128.22 µmol/min. Additionally, Fusarium falciforme AUMC 16563’ pure asparaginase demonstrated anticancer activity against PC-3 (a prostate cell line) with an IC50 of 78.6 µg/mL, HePG-2 (a human hepatocellular carcinoma cell line) with an IC50 of 69.6 µg/mL, HCT-116 (a colon cell line) with an IC50 of 51.5 µg/mL and MCF-7 (a breast cancer cell line) with an IC50 of 32.8 µg/mL. The expression levels of proapoptotic genes (BAX and p53) were significantly greater in the breast cancer cell lines treated with asparaginase than in the negative control breast cancer cell lines.The degree of DNA fragmentation in MCF-7 cells treated with Fusarium falciforme 16563’ pure asparaginase was 27.2 ± 0.69%, and that in MCF-7 cells treated with the drug Doxorubicin 24.1 ± 0.86% was significantly greater than that in the corresponding negative control cells 9.1 ± 1.01%. Finally, the biochemical profiles revealed no impact on the liver or the kidneys. These results suggested that asparaginase had relatively little effect on liver function. All hematological parameters were within normal range during the experiment.ConclusionsThe results of the present study revealed a potent L-ASNase from endophytic F. falciforme isolated from Trifolium alexandrinum, which performs well under a variety of environmental circumstances and can be used in a number of commercial applications.