Human Prostate Cancer Cells Research Articles

Molecular structure, molecular docking, molecular dynamics simulation, and drug likeness evaluation of 3,7-dihydroxy-1,2-dimethoxyxanthone for its anticancer activity

A naturally occurring xanthone, named 3,7-dihydroxy-1,2-dimethoxyxanthone was experimentally and computationally investigated for its anticancer activity. Single crystal X-ray diffraction (XRD) analysis revealed that the compound crystallises in the triclinic space group P1. Vibrational frequencies, electronic properties, chemical reactivity descriptors, the molecular structure, and stability of the compound were investigated by DFT calculations using Gaussian 09 W program at the B3LYP/6–311+G(2d,p) level of theory. All calculations showed correlations to experimental data. Its thermodynamic parameters at various temperatures are presented. The title molecule was docked on the proteins of prostate, cervical, breast, and melanoma cancer cells, and the results showed comparable binding energies to the standard chemotherapeutic agent, doxorubicin with small differences in the range 0.2−0.7 kcal mol−1. Given that the compound showed significant potential on the proteins of prostate and cervical cancer cells, the dynamic properties of the bound state of title ligand with the two selected proteins were further examined through a 200 ns molecular dynamics simulation. The results showed relatively overall higher stability through the simulation time than the free target. All these findings were afterwards confirmed by the good in vitro inhibition activity of the compound against human prostate and cervical cancer cell lines with IC50 values of 9.55 and 9.19 µM, respectively in comparison to the standard drug, and additionally demonstrated innocuousness towards normal human kidney cancer cell lines. Moreover, the drug likeness properties indicated that the title compound has a high bioavailability, a good water solubility, a good gastrointestinal absorption, and can be easily synthesized.

The PP2A regulator IER5L supports prostate cancer progression

Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology. Here, we show that the less studied member of this family, Immediate Early Response 5 like (IER5L), is upregulated in aggressive prostate cancer. Interestingly, the upregulation of IER5L expression exhibits a robust association with metastatic disease in prostate and is recapitulated in other cancer types. In line with this observation, IER5L silencing reduces foci formation, migration and invasion ability in a variety of human and murine prostate cancer cell lines. In vivo, using zebrafish and immunocompromised mouse models, we demonstrate that IER5L-silencing reduces prostate cancer tumor growth, dissemination, and metastasis. Mechanistically, we characterize the transcriptomic and proteomic landscapes of IER5L-silenced cells. This approach allowed us to identify DNA replication and monomeric G protein regulators as downstream programs of IER5L through a pathway that is consistent with the regulation of PP2A. In sum, we report the alteration of IER5L in prostate cancer and beyond and provide biological and molecular evidence of its contribution to tumor aggressiveness.

Tripeptide linked dispiro cyclotriphosphazene conjugates: Synthesis, molecular docking analysis of compounds binding within cancer cell line receptors and in vitro cytotoxic and genotoxic activities

The novel dioxybiphenyl bridged-cyclotriphosphazenes (DPP) bearing tripeptide were synthesized and investigated for their molecular docking analysis, visualizing their binding profiles within various cancer cell line receptors and in vitro cytotoxic and genotoxic properties. The dipeptide compound (Tyr-Phe) was treated with various amino acids to obtain the tripeptide compounds (Tyr-Phe-Gly, Tyr-Phe-Ala, Tyr-Phe-Val, Tyr-Phe-Phe, and Tyr-Phe-Leu). These synthesized tripeptides were subsequently treated with DPP to obtain novel phosphazene compounds bearing tripeptide structures. As a result, the synthesis of target molecules with phosphazene compound in the center and biphenyl and tripeptide groups in the side arms was obtained for the first time in this study. Examining the cytotoxic studies in vitro of our newly synthesized compounds demonstrated the anticancer properties against four selected human cancer cell lines, including breast (MCF-7), ovarian (A2780), prostate (PC-3), and colon (Caco-2) cancer cells. The Comet Assay analysis determined that the cell death mechanism of most of the compounds with cytotoxic activity stemmed from the DNA damage mechanism. Among the compounds, the DPP-Tyr-Phe-Phe compound seems to have the best anticancer activity against the subjected cell lines (Except for A2780) with IC50 values equal to 20.18, 72.14, 12.21, and 5.17 μM against breast, ovarian, prostate, and colon cancer cell lines, respectively. For this reason, the molecular docking analysis was conducted for the DTPP compound to visualize its binding geometry and profile within the target enzyme’s binding site associated with the specific cancer cell line. The analysis revealed that the DTPP derivative exhibited an optimal binding conformation and characteristics within the target enzyme’s binding site, aligning well with the experimental data. Based on the data, these compounds are believed to be strong candidate molecules for both pharmaceutical and clinical applications.

730 nm Light‐Induced Cleavage of BODIPY Photocages via Entropy‐Driven Triplet Sensitization

AbstractLight‐activated drug delivery systems allow precise spatiotemporal control of a drug release process. However, safe and efficient drug release activation needs a low‐power nonpulsed red/near‐infrared light with high tissue penetration depth. Nevertheless, such systems remain a challenge. Herein, a self‐assembled nanovehicle made of 2,6‐diiodo‐B‐dimethyl‐boron dipyrromethene (BODIPY)‐based photocleavable trigonal molecules bearing Pt(II) meso‐tetraphenyltetranaphthoporhyrin photosensitizer and a fluorescent release marker Nile Red in hydrophobic core is introduced. The system employs endothermic triplet–triplet energy transfer between the photosensitizer and the trigonal molecule, leading to the cleavage of the trigonal molecule followed by cargo release. This allows to engage 730 nm light to cleave BODIPY photoremovable protecting groups (PPGs) instead of 530 nm light that would be needed for direct photocage excitation. Therefore, the approach unleashes the desired activation of drug release via photocleavage with longer wavelengths (within the phototherapeutic window) without any chemical modification of the PPGs. Cell studies demonstrate fast intracellular uptake of the nanovehices by PC3 human prostate cancer cells with accumulation in lysosomes in 2 h. Light irradiation at 730 nm on nanovehicles dispersed in cell media leads to payload release. Remarkably, the system exhibits higher release efficiency at low oxygen concentration than at ambient thus allowing to tackle aggressive hypoxic solid tumors.

Diospyros rhodocalyx Kurz induces mitochondrial-mediated apoptosis via BAX, Bcl-2, and caspase-3 pathways in LNCaP human prostate cancer cell line.

Prostate cancer (PCa) is one of the causes of death in men worldwide. Although treatment strategies have been developed, the recurrence of the disease and consequential side effects remain an essential concern. Diospyros rhodocalyx Kurz, a traditional Thai medicine, exhibits diverse therapeutic properties, including anti-cancer activity. However, its anti-cancer activity against prostate cancer has not been thoroughly explored. This study aims to evaluate the anti-cancer activity and underlying mechanisms of the ethyl acetate extract of D. rhodocalyx Kurz (EADR) related to apoptosis induction in the LNCaP human prostate cancer cell line. Ethyl acetate was employed to extract the dried bark of D. rhodocalyx Kurz. The cytotoxicity of EADR on both LNCaP and WPMY-1 cells (normal human prostatic myofibroblast cell line) was evaluated using MTS assay. The effect of EADR on the cell cycle, apoptosis induction, and alteration in mitochondrial membrane potential (MMP) was assessed by the staining with propidium iodide (PI), Annexin V-FITC/PI, and JC-1 dye, respectively. Subsequent analysis was conducted using flow cytometry. The expression of cleaved caspase-3, BAX, and Bcl-2 was examined by Western blotting. The phytochemical profiling of the EADR was performed using gas chromatography-mass spectrometry (GC-MS). EADR exhibited a dose-dependent manner cytotoxic effect on LNCaP cells, with IC50 values of 15.43 and 12.35 µg/mL after 24 and 48 h, respectively. Although it also exhibited a cytotoxic effect on WPMY-1 cells, the effect was comparatively lower, with the IC50 values of 34.61 and 19.93 µg/mL after 24 and 48 h of exposure, respectively. Cell cycle analysis demonstrated that EADR did not induce cell cycle arrest in either LNCaP or WPMY-1 cells. However, it significantly increased the sub-G1 population in LNCaP cells, indicating a potential induction of apoptosis. The Annexin V-FITC/PI staining indicated that EADR significantly induced apoptosis in LNCaP cells. Subsequent investigation into the underlying mechanism of EADR-induced apoptosis revealed a reduction in MMP as evidenced by JC-1 staining. Moreover, Western blotting demonstrated that EADR treatment resulted in the upregulation of BAX, downregulation of BCL-2, and elevation of caspase-3 cleavage in LNCaP cells. Notably, the epilupeol was a prominent compound in EADR as identified by GC-MS. The EADR exhibits anti-cancer activity against the LNCaP human prostate cancer cell line by inducing cytotoxicity and apoptosis. Our findings suggest that EADR promotes apoptosis by upregulating pro-apoptotic BAX, whereas downregulation of anti-apoptotic Bcl-2 results in the reduction of MMP and the activation of caspase-3. Of particular interest is the presence of epilupeol, a major compound identified in EADR, which may hold promise as a candidate for the development of therapeutic agents for prostate cancer.

Splicing variants of versican in CD133+/CD44+ prostate cancer stem cells

A cancer mass is composed of a heterogeneous group of cells, a small part of which constitutes the cancer stem cells since they are less differentiated and have a high capacity to develop cancer. Versican is an extracellular matrix protein located in many human tissues. The mRNA of versican has been shown to have “splicing patterns” as detected by RT-PCR, northern blot analysis, and cDNA sequencing. Based on this knowledge this study aims to reveal the splice variants of versican molecules, which are thought to be involved in the pathogenesis of the DU-145 human prostatic carcinoma cell line and prostatic cancer stem cells isolated from this cell line. In this study, RWPE-1 normal prostatic and DU-145 human prostate cancer cell lines have been used. Prostatic cancer stem cells and the remaining group of non-prostatic-cancer stem cells (bulk population) were isolated according to their CD133+/CD44+. RNA was isolated in all groups, and sequence analysis was accomplished for splicing variants by Illumina NextSeq 500 sequencing system. The results were analyzed by bioinformatic evaluation. As five isoforms of the versican gene in the differential transcript expression are analyzed, it was observed that a significant change was only found in the isoforms Versican 0 and Versican 1. In this study, we explored the function of this molecule which we think to be effective in cancer progression, and suggested that more valuable results can be obtained after the accomplishment of in vivo experiments.

OTUD7B knockdown inhibits proliferation and autophagy through AKT/mTOR signaling pathway in human prostate cancer cell

Prostate cancer (PCa) is the second leading disease of cancer-related death in men around the world, and it is almost impossible to treat advanced PCa. OTUD7B is a member of the deubiquitinase family that undergoes a post-translational transformation process, which is essential for cell stability and signaling and is known to play a critical role in cancer. However, its role in PCa has not been discovered. The aim of the study was to investigate the expression and mechanism of OTUD7B in PCa cells. According to the database, high OTUD7B expression showed a poor prognosis. Therefore, we downregulated OTUD7B using siRNA and confirmed the role of OTUD7B in PC3 prostate cancer cells. OTUD7B knockdown effectively induced apoptosis and inhibited the proliferation in PC3 cells. OTUD7B knockdown inhibited autophagy through AKT/mTOR signaling. We also confirmed the relationship between AKT/mTOR signaling and autophagy through rapamycin, an mTOR inhibitor. Taken together, OTUD7B promotes the proliferation, and autophagy, and inhibits apoptosis of prostate cancer cells via the AKT/mTOR signaling pathway.

Systematic investigation and controlled synthesis of Ag/Ti co-doped hydroxyapatite for bone tissue engineering

Hydroxyapatite (HA) is a cornerstone bio ceramic in bone tissue engineering applications, prized for its inherent biocompatibility and structural resemblance to natural bone tissue. However, both porous and dense, conventional HA formulations face notable stability and mechanical robustness constraints, impeding their broader utility. We introduce an innovative biomaterial synthesized via a straightforward and efficient sol-gel method to surmount these challenges and imbue novel scaffolds with multifunctional capabilities. Leveraging a double doping strategy, our approach seeks to enhance mechanical performance and incorporate antibacterial features, maintaining the biocompatibility of HA-based scaffolds for advanced tissue engineering applications. In pursuit of this objective, we synthesized Ag-doped, Ag, Ti-doped, and Ti-doped HA samples to explore the impact of varying dopant types and concentrations on various structural, thermal, crystallographic, chemical, morphological, mechanical, and biocompatibility characteristics. X-ray Diffraction (XRD) analysis confirmed the presence of apatitic phase compositions across all samples, while Fourier-transform Infrared Spectroscopy (FTIR) data corroborated phosphate formation and functional group identification. Scanning Electron Microscopy (SEM) studies revealed a correlation between particle size and dopant concentration, consistent with XRD findings. Nanoindentation results indicated optimal mechanical performance was achieved with balanced incorporation of Ag and Ti ions despite increased Vickers microhardness with higher Ti concentrations. All doped samples exhibited effective antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), except for the Ti-doped HA sample. Moreover, the HA sample co-doped with equal amounts of Ag and Ti demonstrated noncytotoxicity for human lung cancer (A549) cells. In contrast, all doped samples exhibited cytotoxicity towards human prostate cancer cell (PC3) cells. Statistical analysis confirmed a synergistic enhancement of biocompatibility and mechanical performance in HA samples doped with Ag and Ti ions in equal proportions. In conclusion, our study presents a simple and effective approach for enhancing HA's mechanical and antibacterial properties through co-doping with Ag and Ti. This innovative biomaterial holds significant promise for advancing bone tissue engineering applications.

Quantitative analysis of radiosensitizing effect for magnetic hyperthermia-radiation combined therapy on prostate cancer cells.

Magnetic hyperthermia (MHT) has emerged as a promising therapeutic approach in the field of radiation oncology due to its superior precision in controlling temperature and managing the heating area compared to conventional hyperthermia. Recent studies have proposed solutions to address clinical safety concerns associated with MHT, which arise from the use of highly concentrated magnetic nanoparticles and the strong magnetic field needed to induce hyperthermic effects. Despite these efforts, challenges remain in quantifying therapeutic outcomes and developing treatment plan systems for combining MHTwith radiation therapy (RT). This study aims to quantitatively measure the therapeutic effect, including radiation dose enhancement (RDE) in the magnetic hyperthermia-radiation combined therapy (MHRT), using the equivalent radiation dose (EQD) estimation method. To conduct EQD estimation for MHRT, we compared the therapeutic effects between the conventional hyperthermia-radiation combined therapy (HTRT) and MHRT in human prostate cancer cell lines, PC3 and LNCaP. We adopted a clonogenic assay to validate RDE and the radiosensitizing effect induced by MHT. The data on survival fractions were analyzed using both the linear-quadradic model and Arrhenius model to estimate the biological parameters describing RDE and radiosensitizing effect of MHRT for both cell lines through maximum likelihood estimation. Based on these parameters, a new survival fraction model was suggested forEQD estimation of MHRT. The newly designed model describing the MHRT effect, effectively captures the variations in thermal and radiation dose for both cell lines (R2>0.95), and its suitability was confirmed through the normality test of residuals. This model appropriately describes the survival fractions up to 10Gy for PC3 cells and 8Gy for LNCaP cells under RT-only conditions. Furthermore, using the newly defined parameter r, the RDE effect was calculated as 29% in PC3 cells and 23% in LNCaP cells. EQDMHRT calculated through this model was 9.47Gy for PC3 and 4.71Gy for LNCaP when given 2Gy and MHT for 30 min. Compared to EQDHTRT, EQDMHRT showed a 26% increase for PC3 and a 20% increase for LNCaP. The proposed model effectively describes the changes of the survival fraction induced by MHRT in both cell lines and adequately represents actual data values through residual analysis. Newly suggested parameter r for RDE effect shows potential for quantitative comparisons between HTRT and MHRT, and optimizing therapeutic outcomes in MHRT for prostate cancer.

In vitro biological evaluation of a novel folic acid-targeted receptor quantum dot−β−cyclodextrin carrier for C−2028 unsymmetrical bisacridine in the treatment of human lung and prostate cancers

BackgroundTraditional small-molecule chemotherapeutics usually do not distinguish tumors from healthy tissues. However, nanotechnology creates nanocarriers that selectively deliver drugs to their site of action. This work is the next step in the development of the quantum dot−β−cyclodextrin−folic acid (QD−β−CD−FA) platform for targeted and selected delivery of C−2028 unsymmetrical bisacridine in cancer therapy.MethodsHerein, we report an initial biological evaluation (using flow cytometry and light microscopy) as well as cell migration analysis of QD−β−CD(C−2028)−FA nanoconjugate and its components in the selected human lung and prostate cancer cells, as well as against their respective normal cells.ResultsC−2028 compound induced apoptosis, which was much stronger in cancer cells compared to normal cells. Conjugation of C−2028 with QDgreen increased cellular senescence, while the introduction of FA to the conjugate significantly decreased this process. C−2028 nanoencapsulation also reduced cell migration. Importantly, QDgreen and QDgreen−β−CD−FA themselves did not induce any toxic responses in studied cells.ConclusionsIn conclusion, the results demonstrate the high potential of a novel folic acid-targeted receptor quantum dot−β−cyclodextrin carrier (QDgreen−β−CD−FA) for drug delivery in cancer treatment. Nanoplatforms increased the amount of delivered compounds and demonstrated high suitability.

Therapeutic targets of formononetin for treating prostate cancer at the single-cell level.

Prostate cancer is one of the serious health problems of older male, about 13% of male was affected by prostate cancer. Prostate cancer is highly heterogeneity disease with complex molecular and genetic alterations. So, targeting the gene candidates in prostate cancer in single-cell level can be a promising approach for treating prostate cancer. In the present study, we analyzed the single cell sequencing data obtained from 2 previous reports to determine the differential gene expression of prostate cancer in single-cell level. By using the network pharmacology analysis, we identified the therapeutic targets of formononetin in immune cells and tissue cells of prostate cancer. We then applied molecular docking to determine the possible direct binding of formononetin to its target proteins. Our result identified a cluster of differential gene expression in prostate cancer which can serve as novel biomarkers such as immunoglobulin kappa C for prostate cancer prognosis. The result of network pharmacology delineated the roles of formononetin's targets such CD74 and THBS1 in immune cells' function of prostate cancer. Also, formononetin targeted insulin receptor and zinc-alpha-2-glycoprotein which play important roles in metabolisms of tissue cells of prostate cancer. The result of molecular docking suggested the direct binding of formononetin to its target proteins including INSR, TNF, and CXCR4. Finally, we validated our findings by using formononetin-treated human prostate cancer cell DU145. For the first time, our result suggested the use of formononetin for treating prostate cancer through targeting different cell types in a single-cell level.

Dual electro-/pH-responsive nanoparticle/hydrogel system for controlled delivery of anticancer peptide

An electro-chemo-responsive carrier has been engineered for the controlled release of a highly hydrophilic anticancer peptide, CR(NMe)EKA (Cys-Arg- N-methyl-Glu-Lys-Ala). Remotely controlled on demand release of CR(NMe)EKA, loaded in electro-responsive poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles, has been achieved by applying electrical stimuli consisting of constant positive (+0.50 V) or negative voltages (−0.50 V) at pre-defined time intervals. In addition, after loading CR(NMe)EKA/PEDOT nanoparticles into an injectable pH responsive hydrogel formed by phenylboronic acid grafted to chitosan (PBA-CS), the efficiency of the controlled peptide release has increased approximately by a factor of 2.6. The hydration ratio of such hydrogel is significantly lower in acidic environments than in neutral and basic media, which has been attributed to the dissociation of the boronate bonds between polymer chains. Hence, the electro-controlled peptide release from PBA-CS/CR(NMe)EKA/PEDOT hydrogels, in the acidic environment of tumors, combines the effects of the oxidation and reduction of PEDOT chains on the interactions with the peptide and the carrier, with the peptide concentration gradient at the interface between the collapsed hydrogel and the release medium. Furthermore, the peptide released by electro-stimulation preserved its bioactivity assessed by promoting human prostate cancer cells death. Overall, this work is a promising attempt to develop a carrier platform for small hydrophilic anticancer peptides, which delivery rationale is synergistically regulated by the electrical and pH responsiveness of the carrier.

Ultrasensitive detection of 5-hydroxymethylcytosine in genomic DNA using a graphene-based sensor modified with biotin and gold nanoparticles

Ten-eleven translocation (TET) proteins orchestrate deoxyribonucleic acid (DNA) methylation-demethylation dynamics by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and are frequently inactivated in various cancers. Due to the significance of 5hmC as an epigenetic biomarker for cancer diagnosis, pathogenesis, and treatment, its rapid and precise quantification is essential. Here, we report a highly sensitive electrochemical method for quantifying genomic 5hmC using graphene sheets that were electrochemically exfoliated and functionalized with biotin and gold nanoparticles (Bt-AuNPs) through a single-step electrical method. The attachment of Bt-AuNPs to graphene enhances the specificity of 5hmC-containing DNA and augments the oxidation of 5hmC to 5-formylcytosine in DNA. When coupled to a gold electrode, the Bt-AuNP-graphene-based sensor exhibits exceptional sensitivity and specificity for detecting 5hmC, with a detection limit of 63.2 fM. Furthermore, our sensor exhibits a remarkable capacity to measure 5hmC levels across a range of biological samples, including preclinical mouse tissues with varying 5hmC levels due to either TET gene disruption or oncogenic transformation, as well as human prostate cancer cell lines. Therefore, our sensing strategy has substantial potential for cancer diagnostics and prognosis.

FOXO3a/PI3K/Akt pathway participates in the ROS- induced apoptosis triggered by α-ZEL and β-ZEL

Zearalenone (ZEN), an estrogenic mycotoxin, is one of the most common food and feed contaminants. Also, its metabolites α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) are considered to induce oxidative stress, however its effect in prostate cells is not known yet. Our previous observations showed that forehead box transcription factor 3a (FOXO3a) expression is modified in hormone- sensitive cells in the response to mycotoxins, similar to the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) pathway. Thus, this study evaluated the direct molecular effect of α-ZEL and β-ZEL in a dose of 30 µM in hormone-dependent human prostate cancer (PCa) cells with the focus of the involvement of FOXO3a and PI3K/Akt signaling pathway in that effect. We observed that both active metabolites of ZEN reduced cell viability, induced oxidative stress, cell cycle arrest and apoptosis in PCa cells. Furthermore, we observed that FOXO3a as well as PI3K/Akt signaling pathway participate in ZELs induced toxicity in PCa cells, indicating that this signaling pathway might be a regulator of mycotoxin-induced toxicity generally.

A New Approach to Release Insoluble Curcumin into DU-145 Human Prostate Cancer Cells Through Biodegradable Polymeric Nanocarriers with Apoptosis Induction and Metastasis Inhibition

A New Approach to Release Insoluble Curcumin into DU-145 Human Prostate Cancer Cells Through Biodegradable Polymeric Nanocarriers with Apoptosis Induction and Metastasis Inhibition

Anticancer Effect of Hemin through ANO1 Inhibition in Human Prostate Cancer Cells.

Anoctamin1 (ANO1), a calcium-activated chloride channel, is overexpressed in a variety of cancer cells, including prostate cancer, and is involved in cancer cell proliferation, migration, and invasion. Inhibition of ANO1 in these cancer cells exhibits anticancer effects. In this study, we conducted a screening to identify novel ANO1 inhibitors with anticancer effects using PC-3 human prostate carcinoma cells. Screening of 2978 approved and investigational drugs revealed that hemin is a novel ANO1 inhibitor with an IC50 value of 0.45 μM. Notably, hemin had no significant effect on intracellular calcium signaling and cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, and it showed a weak inhibitory effect on ANO2 at 3 μM, a concentration that completely inhibits ANO1. Interestingly, hemin also significantly decreased ANO1 protein levels and strongly inhibited the cell proliferation and migration of PC-3 cells in an ANO1-dependent manner. Furthermore, it strongly induced caspase-3 activation, PARP degradation, and apoptosis in PC-3 cells. These findings suggest that hemin possesses anticancer properties via ANO1 inhibition and could be considered for development as a novel treatment for prostate cancer.

Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins

Fascaplysin is a red cytotoxic pigment with anticancer properties isolated from the marine sponge Fascaplysinopsis sp. Recently, structure–activity relationship analysis reported by our group suggested that selective cytotoxicity of fascaplysin derivatives towards tumor cells negatively correlates with their ability to intercalate into DNA. To validate this hypothesis, we synthesized 6- and 7-tert-butylfascaplysins which reveal mitigated DNA-intercalating properties. These derivatives were found to be strongly cytotoxic to drug-resistant human prostate cancer cells, albeit did not demonstrate improved selectivity towards cancer cells when compared to fascaplysin. At the same time, kinome analysis suggested an activation of CHK1/ATR axis in cancer cells shortly after the drug exposure. Further experiments revealed induction of replication stress that is eventually converted to the toxic DNA double-strand breaks, resulting in caspase-independent apoptosis-like cell death. Our observations highlight new DNA-targeting effect of some fascaplysin derivatives and indicate more complex structure–activity relationships within the fascaplysin family, suggesting that cytotoxicity and selectivity of these alkaloids are influenced by multiple factors. Furthermore, combination with clinically-approved inhibitors of ATR/CHK1 as well as testing in tumors particularly sensitive to the DNA damage should be considered in further studies.

Cytotoxic activities of metallic nanoparticles biosynthesized using plant extracts and pure compounds from Cephalaria species

Green nanotechnology has been focused on new concepts and fundamental research to produce nanoparticles in high rates and low risks by the use of different sources such as microorganisms and plants. Due to the several constituents in secondary metabolites, plants play an important role in nanomaterial synthesis known as ecofriendly methods which acquired important potential in different studies. The current work aimed to synthesize different silver and zinc-based nanoparticles using Cephalaria tchihatchewii via phytobiological methods involving metallic solutions, organic extracts, and isolated compounds. Sixteen types of nanoparticles were determined in between 50 and 297 nm as diameter and characterized using ultraviolet-visible spectrophotometer, dynamic light scattering, scanning electron microscopy and fourier transform infrared spectroscopy. The cytotoxic activities of nanoparticles were evaluated against human lung cancer (A549), breast cancer (MDA-MB-231), prostate cancer (PC3), and healthy lung (CCD-34Lu) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide MTT assay utilizing doxorubicin as a positive control. Against PC3 cells, the cytotoxic activity of silver nitrate and loganin-AgNPs show significant inhibition with IC50 values of 2.39 ± 0.16 and 7.84 ± 1.21 respectively compared with doxorubicin (12.99 ± 1.57 µg/mL). A moderate inhibition activity was observed for Zinc sulfate, elmalienoside-B-AgNPs, methyl glycoside-AgNPs, and luteolin-7-O-glycoside-AgNPs with IC50 values of 22. 27± 0.18, 11.59 ± 0.82, 12.43 ± 0.37 and 13.26 ± 1.63 µg/mL, respectively. The inhibition activity against human breast cancer cells MDA-MB-231 was significantly reported with silver nitrate (2.25 ± 0.62 µg/mL), and elmalienoside-B-AgNPs (11.48 ± 0.46 µg/mL) compared with doxorubicin (11.61± 0.68 µg/mL). The cytotoxicity activities, make Cephalaria tchihatchewii plant a suitable candidate in different biopharmaceutical usages especially in anticancer activities. This study will provide a clear perspective on nanoparticles containing green synthesized pure compounds and the reaction mechanism of their activities.

Role of KDM2B epigenetic factor in regulating calcium signaling in prostate cancer cells

KDM2B, a histone lysine demethylase, is expressed in a plethora of cancers. Earlier studies from our group, have showcased that overexpression of KDM2B in the human prostate cancer cell line DU-145 is associated with cell adhesion, actin reorganization, and improved cancer cell migration. In addition, we have previously examined changes of cytosolic Ca2+, regulated by the pore-forming proteins ORAI and the Ca2+ sensing stromal interaction molecules (STIM), via store-operated Ca2+ entry (SOCE) in wild-type DU-145. This study sought to evaluate the impact of KDM2B overexpression on the expression of key molecules (SGK1, Nhe1, Orai1, Stim1) and SOCE. Furthermore, this is the first study to evaluate KDM2B expression in circulating tumor cells (CTCs) from patients with prostate cancer. mRNA levels for SGK1, Nhe1, Orai1, and Stim1 were quantified by RT-PCR. Calcium signals were measured in KDM2B-overexpressing DU-145 cells, loaded with Fura-2. Blood samples from 22 prostate cancer cases were scrutinized for KDM2B expression using immunofluorescence staining and the VyCAP system. KDM2B overexpression in DU-145 cells increased Orai1, Stim1, and Nhe1 mRNA levels and significantly decreased Ca2+ release. KDM2B expression was examined in 22 prostate cancer patients. CTCs were identified in 45 % of these patients. 80 % of the cytokeratin (CK)-positive patients and 63 % of the total examined CTCs exhibited the (CK + KDM2B + CD45−) phenotype. To conclude, this study is the first to report increased expression of KDM2B in CTCs from patients with prostate cancer, bridging in vitro and preclinical assessments on the potentially crucial role of KDM2B on migration, invasiveness, and ultimately metastasis in prostate cancer.

The Role of Folic Acid on PC3 Prostate Cancer Cell Line

Aim: Prostate cancer (PCa), one of the most common malignant solid tumors, has become a significant and rapidly increasing global health concern for men. One of the vitamins in the B group that is essential in decreasing the risk of cancer is folic acid (FA). However, the protective effects of FA against PCa are insufficiently examined, and the underlying mechanism is still unknown. In this study, androgen-nonresponsive (PC3) human PCa was used to get a better understanding of the effect of FA on cell proliferation. Material and Method: In the present study, the MTT assay was used to assess FA's inhibitory effect on cellular proliferation. Additionally, all groups underwent the TUNEL immunofluorescence staining procedure to identify apoptosis in the PC3 cell line. Results: The most appropriate cytotoxic dose was determined to be the 24-hour FA values. When apoptotic TUNEL staining was evaluated in the PC3 cell line, FA significantly increased apoptosis. There was not a significant difference observed between the docetaxel (Dtx) and FA groups in terms of TUNEL-positive cell immunoreactivity in the PC3 cell line. There was no apparent distinction in the immunreactivity intensity of TUNEL-positive cells in these groups. Conclusion: The present study provides a fresh perspective on the fundamental mechanism underlying FA's capability to prevent PC3 cancer cells from proliferating. Our findings suggest that FA effectively inhibits PC3 cell line proliferation through the upregulation of apoptosis. Consequently, FA may be a potential novel cytotoxic and therapeutic strategy in the treatment of PCa disease.