Nanocarrier - Mediated Salinomycin Delivery Induces Apoptosis and Alters EMT Phenomenon in Prostate Adenocarcinoma.

Salinomycin (Sal) has been recently discovered as a novel chemotherapeutic agent against various cancers including prostate cancer which is one of the most commonly diagnosed cancers affecting male populations worldwide. Herein we designed salinomycin nanocarrier (Sal-NPs) to extend its systemic circulation and to increase its anticancer potential. Prepared nanoform showed high encapsulation and sustained release profile for salinomycin. The present study elucidated the cytotoxicity and mechanism of apoptotic cell death of Sal-NPs against prostate cancer both in vitro and in vivo. At all measured concentrations, Sal-NPs showed more significant cytotoxicity to DU145 and PC3 cells than Sal alone. This effect was mediated by apoptosis, as confirmed by ROS generation, loss of MMP and cell cycle arrest at the G1 phase in both cells. Sal-NPs efficiently inhibited migration of PC3 and DU145 cells via effectively downregulating the epithelial mesenchymal transition. Also, the results confirmed that Sal-NPs can effectively inhibit the induction of Prostate adenocarcinoma in male Wistar rats. Sal-NPs treatment exhibited a decrease in tumour sizes, a reduction in prostate weight, and an increase in body weight, which suggests that Sal-NPs is more effective than salinomycin alone. Our results suggest that the molecular mechanism underlying the Sal-NPs anticancer effect may lead to the development of a potential therapeutic strategy for treating prostate adenocarcinoma.

Monitoring of singlet oxygen generation of a novel Schiff-base substituted silicon phthalocyanines by sono-photochemical studies and in vitro activities on prostate cancer cell.

This study demonstrates the potential of sono-photodynamic therapy as an effective approach for enhancing singlet oxygen generation using the synthesized Schiff-base diaxially substituted silicon phthalocyanines. In photochemical studies, the singlet oxygen quantum yields (Φ∆) were determined as 0.43 for Si1a, 0.94 for Q-Si1a, 0.58 for S-Si1a, and 0.49 for B-Sia1. In sono-photochemical studies, the Φ∆ values were reached to 0.67 for Si1a, 1.06 for Q-Si1a, 0.65 for S-Si1a, and 0.67 for B-Sia1. In addition, this study demonstrates the therapeutic efficacy of phthalocyanines synthesized as sensitizers on the PC3 prostate cancer cell line through in vitro experiments. The application of these treatment modalities exhibited notable outcomes, leading to a substantial decrease in cell viability within the PC3 prostate cancer cell line. These findings highlight the potential of utilizing these synthesized phthalocyanines as promising therapeutic agents for prostate cancer treatment.

First in vitro measurement of VHEE relative biological effectiveness (RBE) in lung and prostate cancer cells using the ARES linac at DESY.

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

Inhibition of Prostate Cancer Cell Survival and Proliferation by Carnosic Acid Is Associated with Inhibition of Akt and Activation of AMPK Signaling.

Prostate cancer, accounting for 375,304 deaths in 2020, is the second most prevalent cancer in men worldwide. While many treatments exist for prostate cancer, novel therapeutic agents with higher efficacy are needed to target aggressive and hormone-resistant forms of prostate cancer, while sparing healthy cells. Plant-derived chemotherapy drugs such as docetaxel and paclitaxel have been established to treat cancers including prostate cancer. Carnosic acid (CA), a phenolic diterpene found in the herb rosemary (Rosmarinus officinalis) has been shown to have anticancer properties but its effects in prostate cancer and its mechanisms of action have not been examined. CA dose-dependently inhibited PC-3 and LNCaP prostate cancer cell survival and proliferation (IC50: 64, 21 µM, respectively). Furthermore, CA decreased phosphorylation/activation of Akt, mTOR, and p70 S6K. A notable increase in phosphorylation/activation of AMP-activated kinase (AMPK), acetyl-CoA carboxylase (ACC) and its upstream regulator sestrin-2 was seen with CA treatment. Our data indicate that CA inhibits AKT-mTORC1-p70S6K and activates Sestrin-2-AMPK signaling leading to a decrease in survival and proliferation. The use of inhibitors and small RNA interference (siRNA) approaches should be employed, in future studies, to elucidate the mechanisms involved in carnosic acid's inhibitory effects of prostate cancer.

Vikil 20 Suppresses the Proliferation of Prostate Cancer (PC-3) Cells and Quenches Free Radicals In Vitro.

Vikil 20 is an herbal formula produced in Ghana and is widely marketed as a product to boost immunity as well as for general well-being. However, the pharmacological effect of this herbal preparation has not been proven scientifically. Therefore, this study was aimed at investigating the antioxidative as well as the anti-prostate cancer effects of the product. To assess the antioxidative effect of Vikil 20, the DPPH and ABTS activities were investigated. The total phenolic content was investigated using the Folin-Ciocalteu method. The cytotoxic effect of Vikil 20 against prostate cancer (PC-3) cells as well as normal (RAW 264.7) cells was investigated using the MTT assay whereas its anti-metastatic effect was analyzed using the cell migration assay. The effect of Vikil 20 on cell adhesion was analyzed via the cell adhesion assay whereas its effect on TNF-α secretion was investigated using a TNF-α detection kit. Vikil 20 demonstrated significant antioxidant effects by suppressing 57.61% and 92.88% respectively of DPPH and ABTS radicals at 1000 µg/mL with total phenolic contents of 140.45 mg GAE/g. Vikil 20 suppressed the proliferation of PC-3 cells by reducing the number of viable cells to 49.5% while sparing the RAW, 264.7 cells. Further, Vikil 20 significantly suppressed both cellular migration and adhesion of prostate cancer cells. Finally, suppression of cellular migration and adhesion is associated with a reduction in TNF-α secretion by PC-3 cells. Taken together, Vikil 20 was found to possess significant antioxidant and anti-prostate cancer effects in vitro.

Synthesis, characterisation and in vitro anticancer activity of conjugated protease inhibitor-silver nanoparticles (AgNPs-PI) against human breast MCF-7 and prostate PC-3 cancer cell lines.

The conjugated silver nanoparticles using biomolecules have attracted great attention of researchers because physical dimensions and surface chemistry play important roles in toxicity and biocompatibility of AgNPs. Hence, in the current study, synthesis of bio-conjugated AgNPs with protein protease inhibitor (PI) isolated from Streptomyces spp. is reported. UV-visible spectra of PI and AgNPs showed stronger peaks at 280 and 405 nm, confirming the synthesis of conjugated AgNPs-PI. TEM and SEM images of AgNPs-PI showed spherical-shaped nanoparticles with a slight increase in particle size and thin amorphous layer around the surface of silver nanomaterial. Circular dichroism, FT-IR and fluorescence spectral studies confirmed AgNPs-PI conjugation. Conjugated AgNPs-PI showed excellent anticancer potential than AgNPs and protease inhibitor separately on human breast MCF-7 and prostate PC-3 cell lines. The findings revealed that surface modification of AgNPs with protein protease inhibitor stabilised the nanomaterial and increased its anticancer activity.

Novel Metabolites from the Marine-Derived Fungus Peniophora sp. SCSIO41203 Show Promising In Vitro Antitumor Activity as Methuosis Inducers in PC-3 Cells.

Two new cytochalasin derivatives, peniotrinins A (1) and B (2), three new citrinin derivatives, peniotrinins C-E (4, 5, 7), and one new tetramic acid derivative, peniotrinin F (12), along with nine structurally related known compounds, were isolated from the solid culture of Peniophora sp. SCSIO41203. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis, quantum chemical calculations, and the calculated ECD. Interestingly, 1 is the first example of a rare 6/5/5/5/6/13 hexacyclic cytochalasin. We screened the above compounds for their anti-prostate cancer activity and found that compound 3 had a significant anti-prostate cancer cell proliferation effect, while compounds 1 and 2 showed weak activity at 10 µM. We then confirmed that compound 3 exerts its anti-prostate cancer effect by inducing methuosis through transmission electron microscopy and cellular immunostaining, which suggested that compound 3 might be first reported as a potential anti-prostate methuosis inducer.

Effects of metformin and silodosin as supplementary treatments to abiraterone on human telomerase reverse transcriptase (hTERT) level in metastatic castration-resistant prostate cancer (mCRPC) cells: An in vitro study.

The antiproliferative properties of metformin and silodosin have been observed in prostate cancer. Furthermore, it is hypothesized that the molecular pathways related to these drugs may impact the levels of human telomerase reverse transcriptase (hTERT) in prostate cancer cells. The aim of this study was to assess the effect of metformin and silodosin on the levels of hTERT in metastatic castration-resistant prostate cancer (mCRPC) cells. The present study employed an experimental design with a post-test-only control group. This study utilized the PC3 cell line as a model for mCRPC. A viability experiment was conducted using the CCK-8 method to determine the inhibitory concentration (IC50) values of metformin, silodosin, and abiraterone acetate (AA) after a 72-hour incubation period of PC3 cells. In order to investigate the levels of hTERT, PC3 cells were divided into two control groups: a negative control and a standard therapy with AA. Additionally, three experimental combination groups were added: metformin with AA; silodosin with AA; and metformin, silodosin and AA. The level of hTERT was measured using sandwich ELISA technique. The difference in hTERT levels was assessed using ANOVA followed by a post hoc test. The IC50 values for metformin, silodosin, and AA were 17.7 mM, 44.162 mM, and 66.9 µM, respectively. Our data indicated that the combination of metformin with AA and the combination of metformin, silodosin and AA decreased the hTERT levels when compared to control, AA, and silodosin with AA. The administration of metformin resulted in a reduction of hTERT levels in the PC3 cell line, but the impact of silodosin on hTERT levels was not statistically significant compared to AA group.

[Study of antitumor effects of human placenta hydrolysate on PC-3, OAW-42, BT-474 cell cultures].

AIM: To investigate the antitumor effects of human placenta hydrolysate (HPH) peptides on three hormone-dependent human cell lines: prostate adenocarcinoma, breast carcinoma, and ovarian cancer by metabolic analysis of cell cultures. MATERIALS AND METHODS: The effect of HPH on tumor and control tumor cell lines was evaluated. Study stages: (A) de novo peptide sequencing by collision-induced dissociation mass spectrometry; (B) detection of peptides with anti-tumor properties; (C) expert analysis of the obtained lists of peptides. RESULTS: Dose-dependent cytotoxic effects of HPH on three tumor cell lines are shown: PC-3 (human prostate adenocarcinomas), OAW-42 (human ovarian cancer), BT-474 (human breast carcinomas), and IC50 constants (1.3-2.8 mg/ml) were obtained. The analysis of the HPH peptide fraction showed more than 70 peptides with antitumor properties in the composition of this HPH, including kinase inhibitors: mitogen-activated protein kinases, kappa-bi nuclear factor inhibitor kinase, AKT serine/threonine kinase 1, protein kinase C zeta, interleukin-1 receptor-associated kinase 4 and cyclin-dependent kinase 1. CONCLUSION: The results of the study indicate not only the oncological safety of the HPH used in therapy but also the mild antitumor effects of this HPH at high concentrations.

Potential antiprostatic performance of novel lanthanide-complexes based on 5-nitropicolinic acid.

Two new lanthanide-complexes based on the 5-nitropicolinate ligand (5-npic) were obtained and fully characterized. Single-crystal X-ray diffraction revealed that these compounds are isostructural to a Dy-complex, previously published by us, based on dinuclear monomers link together with an extended hydrogen bond network, providing a final chemical formula of [Ln2(5-npic)6(H2O)4]·(H2O)2, where Ln = Dy (1), Gd (2), and Tb (3). Preliminary photoluminescent studies exhibited a ligand-centered emission for all complexes. The potential antitumoral activity of these materials was assayed in a prostatic cancer cell line (PC-3; the 2nd most common male cancerous disease), showing a significant anticancer activity (50-60% at 500 µg·mL-1). In turn, a high biocompatibility by both, the complexes and their precursors in human immunological HL-60 cells, was evidenced. In view of the strongest toxic effect in the tumoral cell line provided by the free 5-npic ligand (~ 40-50%), the overall anticancer complex performance seems to be triggered by the presence of this molecule.

Cytosine Deaminase-Overexpressing hTERT-Immortalized Human Adipose Stem Cells Enhance the Inhibitory Effects of Fluorocytosine on Tumor Growth in Castration Resistant Prostate Cancer.

A promising de novo approach for the treatment of Castration-resistant prostate cancer (CRPC) exploits cell-mediated enzyme prodrug therapy comprising cytosine deaminase (CD) and fluorouracil (5-FC). The aim of this study was to determine the potential of bacterial CD-overexpressing hTERT-immortalized human adipose stem cells (hTERT-ADSC.CD) to suppress CRPC. A lentiviral vector encoding a bacterial CD gene was used to transfect and to generate the hTERT-ADSC.CD line. The ability of the cells to migrate selectively towards malignant cells was investigated in vitro. PC3 and hTERT-ADSC.CD cells were co-cultured. hTERT-ADSC.CD and 1 × 106 PC3 cells were administered to nude mice via intracardiac and subcutaneous injections, respectively, and 5-FC was given for 14 days. hTERT-ADSC.CD were successfully engineered. Enhanced in vitro hTERT-ADSC.CD cytotoxicity and suicide effect were evident following administration of 5 µM 5-FC. hTERT-ADSC.CD, together with 5-FC, augmented the numbers of PC3 cells undergoing apoptosis. In comparison to controls administered hTERT-ADSC.CD monotherapy, hTERT-ADSC.CD in combination with 5-FC demonstrated a greater suppressive effect on tumor. In CPRC-bearing mice, tumor suppression was enhanced by the combination of CD-overexpressing ADSC and the prodrug 5-FC. Stem cells exhibiting CD gene expression are a potential novel approach to treatment for CRPC.

Effects of Red Sorghum-Derived Deoxyanthocyanidins and Their O-ß-D-Glucosides on E-Cadherin Promoter Activity in PC-3 Prostate Cancer Cells.

Although much less common than anthocyanins, 3-Deoxyanthocyanidins (3-DAs) and their glucosides can be found in cereals such as red sorghum. It is speculated that their bioavailability is higher than that of anthocyanins. Thus far, little is known regarding the therapeutic effects of 3-DAs and their O-ß-D-glucosides on cancer, including prostate cancer. Thus, we evaluated their potential to decrease cell viability, to modulate the activity of transcription factors such as NFκB, CREB, and SOX, and to regulate the expression of the gene CDH1, encoding E-Cadherin. We found that 4',7-dihydroxyflavylium chloride (P7) and the natural apigeninidin can reduce cell viability, whereas 4',7-dihydroxyflavylium chloride (P7) and 4'-hydroxy-7-O-ß-D-glucopyranosyloxyflavylium chloride (P3) increase the activities of NFkB, CREB, and SOX transcription factors, leading to the upregulation of CDH1 promoter activity in PC-3 prostate cancer cells. Thus, these compounds may contribute to the inhibition of the epithelial-to-mesenchymal transition in cancer cells and prevent the metastatic activity of more aggressive forms of androgen-resistant prostate cancer.

Antitumor activity of essential oils-based nanostructured lipid carriers on prostate cancer cells.

Prostate cancer (PCa) is the second most frequent malignancy in men worldwide. Essential oils (EOs) are natural products which can act in cancer suppression by several mechanisms. In this work, a nanotechnological approach was used to develop and evaluate the antineoplastic effects of EOs loaded by nanostructured lipid carriers (NLCs). Three different NLC systems composed of cinnamon, sage or thyme EOs were optimized using factorial design (23). The optimal formulations were characterized in terms of biophysical parameters, structure, stability, in vivo safety and efficacy. All optimized NLC formulations exhibited excellent structural properties and stability over a year (25 °C). They proved to be in vitro and in vivo biocompatible on PNT2 normal prostate cells and on chicken embryos (CE), respectively. In PC3 PCa cells, optimized NLCs inhibited cell proliferation and migration and changed its morphology. In CE xenograft tumor, NLCs have inhibited tumor growth and angiogenesis. The results from this work suggested that all developed EO-based NLC formulations had their stability improved while the biological activity remains unchanged.

Antiproliferative and Apoptotic Effects of Murici (Byrsonima crassifolia (L.) Kunth and verbascifolia (L.) DC) and Taperebá (Spondias mombin L.) Extracts in Human Prostate Cell Line (PC-3).

OBJECTIVE: The present study aimed to evaluate the antiproliferative and apoptotic effects of extracts obtained from the murici (Byrsonima crassifolia (L.) Kunth and verbascifolia (L.) DC) and taperebá (Spondias mombin L.) pulps, on cell proliferation, cell cycle and apoptosis on human prostate cell line (PC-3). METHODS: Four extract was produced from the pulps:  murici aqueous extract (MA), taperebá aqueous extract (TA), murici ethanolic extract (ME) and taperebá ethanolic extract (TE). In the present study, the analysis of cell viability, cell cycle and apoptosis analyze were performed using the MTT method and flow cytometry. RESULTS: The results showed that murici and taperebá extracts proved to be inhibitors of cell growth, modulation of cell cycle promoters and capable of enhancing the death in prostate carcinoma cells PC-3; suggesting a regulatory effect in prostate cell line, depending on type of extract and dosage used. CONCLUSION: These results open a series of perspectives on the use of these bioactive extracts in the prevention and treatment of prostate cancer.

Synthesis and Validation of TRIFAPYs as a Family of Transfection Agents for Therapeutic Oligonucleotides.

Transfection agents play a crucial role in facilitating the uptake of nucleic acids into eukaryotic cells offering potential therapeutic solutions for genetic disorders. However, progress in this field needs the development of improved systems that guarantee efficient transfection. Here, we describe the synthesis of a set of chemical delivery agents (TRIFAPYs) containing alkyl chains of different lengths based on the 1,3,5-tris[(4-alkyloxy-1pyridinio)methyl]benzene tribromide structure. Their delivery properties for therapeutic oligonucleotides were evaluated using PolyPurine Reverse Hoogsteen hairpins (PPRHs) as a silencing tool. The binding of liposomes to PPRHs was evaluated by retardation assays in agarose gels. The complexes had a size of 125 nm as determined by DLS, forming well-defined concentrical vesicles as visualized by Cryo-TEM. The prostate cancer cell line PC-3 was used to study the internalization of the nanoparticles by fluorescence microscopy and flow cytometry. The mechanism of entrance involved in the cellular uptake was mainly by clathrin-mediated endocytosis. Cytotoxicity analyses determined the intrinsic toxicity caused by each TRIFAPY and the effect on cell viability upon transfection of a specific PPRH (HpsPr-C) directed against the antiapoptotic target survivin. TRIFAPYs C12-C18 were selected to expand these studies in the breast cancer cell line SKBR-3 opening the usage of TRIFAPYs for both sexes and, in the hCMEC/D3 cell line, as a model for the blood-brain barrier. The mRNA levels of survivin decreased, while apoptosis levels increased upon the transfection of HpsPr-C with these TRIFAPYs in PC-3 cells. Therefore, TRIFAPYs can be considered novel lipid-based vehicles for the delivery of therapeutic oligonucleotides.

Co-targeting SKP2 and KDM5B inhibits prostate cancer progression by abrogating AKT signaling with induction of senescence and apoptosis.

BACKGROUND: Prostate cancer (PCa) is the second-leading cause of cancer mortalities in the United States and is the most commonly diagnosed malignancy in men. While androgen deprivation therapy (ADT) is the first-line treatment option to initial responses, most PCa patients invariably develop castration-resistant PCa (CRPC). Therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the anticancer effects of the combination of two small molecule inhibitors, SZL-P1-41 (SKP2 inhibitor) and PBIT (KDM5B inhibitor), on PCa suppression and to delineate the underlying molecular mechanisms. METHODS: Human CRPC cell lines, C4-2B and PC3 cells, were treated with small molecular inhibitors alone or in combination, to assess effects on cell proliferation, migration, senescence, and apoptosis. RESULTS: SKP2 and KDM5B showed an inverse regulation at the translational level in PCa cells. Cells deficient in SKP2 showed an increase in KDM5B protein level, compared to that in cells expressing SKP2. By contrast, cells deficient in KDM5B showed an increase in SKP2 protein level, compared to that in cells with KDM5B intact. The stability of SKP2 protein was prolonged in KDM5B depleted cells as measured by cycloheximide chase assay. Cells deficient in KDM5B were more vulnerable to SKP2 inhibition, showing a twofold greater reduction in proliferation compared to cells with KDM5B intact (p < 0.05). More importantly, combined inhibition of KDM5B and SKP2 significantly decreased proliferation and migration of PCa cells as compared to untreated controls (p < 0.005). Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of both cellular senescence and apoptosis, which was measured via Western blot analysis and senescence-associated ß-galactosidase (SA-ß-Gal) staining. CONCLUSIONS: Combined inhibition of KDM5B and SKP2 was more effective at inhibiting proliferation and migration of CRPC cells, and this regimen would be an ideal therapeutic approach of controlling CRPC malignancy.

Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

Response surface methodology optimizes selenium inhibition of prostate cancer PC-3 cell viability.

BACKGROUND: The rising incidence of prostate cancer in the U.S. necessitates innovative therapeutic approaches to this disease. Though extensive research has studied Selenium as an anticarcinogen against prostate cancer, results have varied due to overlooked experimental confounds. Recent studies have identified differential effects of various selenium compounds on prostate cancer cells. This study leverages Mixture Design Response Surface Methodology to characterize the ideal combination of select Se forms against the PC-3 prostate cancer cell line. METHODS: The PC-3 cell line was chosen as a model for its representation of advanced-stage malignancy. Three Se compounds-sodium selenite, methylseleninic acid, and nano-selenium-were selected for their promising antineoplastic potential. Nano-Se particles were synthesized and subsequently characterized by transmission electron microscopy. Cells were cultured, treated with Se compounds, and assessed for viability using an Alamar Blue Assay. IC50 values of individual Se compounds were determined, and treatment combinations evaluated. In collaboration with statical modeling experts, MDRSM was utilized to optimize Se compound combinations. RESULTS: Absolute IC50 values were identified for methylseleninic acid (5.01 µmol/L), sodium selenite (13.8 µmol/L), and nano-selenium (14.6 µmol/L). Combining methylseleninic acid and sodium selenite resulted in only 5% PC-3 cell viability, whereas individual treatments reduced viability by approximately 45%. Among the tested mixtures, the 50:50 combination of MSA and sodium selenite most effectively decreased PC-3 cell viability. Regression analysis indicated the special cubic model had a strong fit (multiple r² = 0.9853), predicting maximum cell viability reduction from the methylseleninic acid and selenite mixture. CONCLUSION: The specific form of Selenium plays a pivotal role in determining its physiological effects and therapeutic potential against prostate cancer. All three selenium compounds showed variable antineoplastic effects, with a 50:50 mixture of methylseleninic acid and selenite exhibiting optimal results. Nano-selenium, when combined with selenite, showed no additive effect, implying a shared mechanism of action. Our research underscores the critical need to consider Se compound forms as distinct entities in prostate cancer treatment and encourages further exploration of Se compounds against prostate cancer.

Overexpression of Transmembrane Phosphatase with Tensin homology (TPTE) in prostate cancer is clinically significant, suggesting its potential as a valuable biomarker.

PURPOSE: Cancer testis antigens (CTAs) are a family of proteins typically expressed in male testicles but overexpressed in various cancer cell types. Transmembrane Phosphatase with Tensin homology (TPTE) is expressed only in the testis of healthy individuals and is a member of the family of CTAs. The current study, for the first time, examined the significance of TPTE expression in prostate cancer (PCa) tissues by generating a novel antibody marker targeting TPTE protein. METHODS: Polyclonal antibodies were prepared for TPTE-p1 and TPTE-p2 peptides, which are derived from the extracellular domains of TPTE. Anti-TPTE-p2 antibody was then used to study the extent and pattern of TPTE expression in 102 PCa and 48 benign prostatic hyperplasia (BPH) tissue samples by immunohistochemistry. The viability of cancer cell lines (PC-3 and MCF-7 cells) was also evaluated in the presence of anti-TPTE-p2 antibody using the MTT test. RESULTS: The immunohistochemical analysis demonstrated a significant increase in cytoplasmic and membrane TPTE expression in the PCa samples compared to the BPH group (both P < 0.0001). Cytoplasmic TPTE expression was positively correlated with Gleason score and PSA levels (P = 0.03 and P = 0.001, respectively). Significant correlations were identified between the levels of PSA and perineural invasion and the membrane expression (P = 0.01, P = 0.04, respectively). Moreover, anti-TPTE-p2 antibody inhibited PC-3 and MCF-7 cells proliferation compared to the control group for 24 h (P < 0.001 and P = 0.001, respectively) as well as for 48 h (P = 0.001 and P = 0.001, respectively). CONCLUSION: Our findings indicate that increased TPTE expression is associated with progression of disease. The ability of anti-TPTE-p2 antibody to recognize and target the TPTE protein makes it a potential biomarker to assess and/or target the PCa.

Proliferation and migration of PC-3 prostate cancer cells is counteracted by PPARγ-cladosporol binding-mediated apoptosis and a decreased lipid biosynthesis and accumulation.

OBJECTIVES: Chemoprevention, consisting of the administration of natural and/or synthetic compounds, appears to be an alternative way to common therapeutical approaches to preventing the occurrence of various cancers. Cladosporols, secondary metabolites from Cladosporium tenuissimum, showed a powerful ability in controlling human colon cancer cell proliferation through a peroxisome proliferator-activated receptor gamma (PPARγ)-mediated modulation of gene expression. Hence, we carried out experiments to verify the anticancer properties of cladosporols in human prostate cancer cells. Prostate cancer represents one of the most widespread tumors in which several risk factors play a role in determining its high mortality rate in men. MATERIALS AND METHODS: We assessed, by viability assays, PPARγ silencing and overexpression experiments and western blotting analysis, the anticancer properties of cladosporols in cancer prostate cell lines. RESULTS: Cladosporols A and B selectively inhibited the proliferation of human prostate PNT-1A, LNCaP and PC-3 cells and their most impactful antiproliferative ability towards PC-3 prostate cancer cells, was mediated by PPARγ modulation. Moreover, the anticancer ability of cladosporols implied a sustained apoptosis. Finally, cladosporols negatively regulated the expression of enzymes involved in the biosynthesis of fatty acids and cholesterol, thus enforcing the relationship between prostate cancer development and lipid metabolism dysregulation. CONCLUSION: This is the first work, to our knowledge, in which the role of cladosporols A and B was disclosed in prostate cancer cells. Importantly, the present study highlighted the potential of cladosporols as new therapeutical tools, which, interfering with cell proliferation and lipid pathway dysregulation, may control prostate cancer initiation and progression.