Prostate Carcinoma Cell Lines Research Articles

QbD-driven Formulation Development and Evaluation of Genistein Nanoparticles for Prostate Cancer

Background: Genistein (GEN) shows significant anticancer potential, particularly against prostate cancer. However, its clinical application is limited by poor water solubility, rapid metabolism and excretion, low bioavailability, and lack of targeted delivery to cancer cells, hindering its effectiveness as a chemopreventive or therapeutic agent. Objective: In this study, poly-ε-caprolactone (PCL) nanoparticles incorporating polyvinyl alcohol (PVA) as a stabilizer were engineered to encapsulate genistein (GEN) effectively. Utilizing a Quality by Design (QbD) methodology, the development and optimization of these nanoparticles were systematically approached. Methods: GEN-loaded PCL nanoparticles (NPs) were prepared using the Solvent Evaporation Technique, ideal for encapsulating hydrophobic drugs. A Plackett–Burman design (PBD) identified key factors, followed by a Box–Behnken design (BBD) to optimize nanoparticle quality. The NPs were evaluated for particle size, zeta potential (ZP), polydispersity index (PDI), morphology, encapsulation efficiency (EE), in vitro drug release, and cytotoxicity. Results: The optimized formulation containing PCL, PVA, and Volume of organic solvent as 43.7 mg, 6.2 mg, and 10.0 ml, respectively was chosen because it showed EE (%) of 94.0%, average particle size of 150 nm, PDI of 0.10, ZP of -28.0 and exhibited sustained release of GEN for around four days. The antiproliferative activities of GEN PCL NPs were confirmed by the MTT test in vitro on malignant prostate carcinoma cell lines (PC3). Flow cytometric analysis showed that the inhibition of cell proliferation of more potent GEN PCL NPs is comparable with the effects of free GEN. Conclusion: The findings indicate that genistein-loaded PCL nanoparticles have the potential to augment the anticancer efficacy of genistein, both in vitro and in vivo. This suggests their promise as a viable candidate for prostate cancer treatment.

In Vitro Antitumor Effect of Oils Rich in CBD and THC Cannabis Extract in Canine Prostate Carcinoma Cell Lines

Prostate cancer is one of the leading causes of cancer-related deaths worldwide, even when diagnosed at an early stage in humans and dogs. Dogs have a significant incidence of spontaneous prostate cancer, which is highly similar to human androgen-independent prostate cancer and represents a valuable model for comparative studies. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two main cannabinoids extracted from Cannabis sativa and have demonstrated antiproliferative and anti-invasive properties in different tumor types. In this study, CBD or THC-rich extracts inhibited the proliferation of two canine prostatic carcinoma cell lines, PC1 and PC2, showing an IC50 of 3.43 and 3.57 μM for CBD rich extracts, and 4.90 and 4.48 μM THC rich extracts, respectively. Cell death was also observed with both Annexin V and Propidium iodide staining for the canine cell lines. These results provide new information concerning the use of rich oil in canine PC and open a promising opportunity for further in vitro and in vivo studies to establish the mechanisms of action of these compounds using dogs as a natural model for prostatic carcinoma.

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.

Influence of extraction solvents on the chemical constituents and biological activities of Astragalus aduncusfrom Turkey flora: In vitro and in silico insights.

The n-hexane, ethyl acetate, ethanol, ethanol/water (70% ethanol), and water extracts of Astragalus aduncus aerial parts were investigated for their antioxidant potential, enzyme inhibition activity (anti-acetylcholinesterase [AChE], anti-butyrylcholinesterase [BChE],antityrosinase, antiamylase, and antiglucosidase) and antiproliferative effect (against colon adenocarcinoma cell line[HT-29], gastric cancer cell line[HGC-27], prostate carcinoma cell line[DU-145], breast adenocarcinoma cell line[MDA-MB-231],and cervix adenocarcinoma cell line [HeLa]). In addition, the phytochemical profile of the extracts was evaluated using validated spectrophotometric and high-pressure liquid chromatography-electrospray ionization/tandem mass spectroscopymethods. Generally, the 70% ethanol extract demonstrated the strongest antioxidant properties, and it was the richest source of total phenolic constituents. Our findings indicated that the ethyl acetate extract was the most potent BChE inhibitor (11.44 mg galantamine equivalents [GALAE]/g) followed by the ethanol extract (8.51 mg GALAE/g), while the ethanol extract was the most promising AChE inhibitor (3.42 mg GALAE/g) followed by the ethanol/water extract (3.17 mg GALAE/g).Excellent tyrosinase inhibitory activity (66.25 mg kojic acid equivalent/g) was observed in ethanol/water extracts of the aerial part of A. aduncus. Тhese results showed that the most cytotoxic effects were exhibited by the ethyl acetate extract against HGC-27 cells (IC50: 36.76 µg/mL), the ethanol extract against HT-29 cells (IC50: 30.79 µg/mL), and the water extract against DU-145 cells (IC50: 37.01 µg/mL). A strong correlation was observed between the highest total flavonoid content and the highest content of individual compounds in the ethanol extract, including rutin, hyperoside, isoquercitrin, delphinidin-3,5-diglucoside (delphinidin-3,5-O-diglucoside), and kaempferol-3-glucoside (kaempferol-3-O-glucoside). In the present study, the A. aduncus plant was considered a new source of antioxidants, enzyme inhibitors, and anticancer agents and could be used as a future health-benefit natural product.

Designing a Temporin-1CEa Analog with Improved in Vitro Selectivity towards Prostate Cancerous Cell Line (LNCaP)

Temporins are small antimicrobial peptides which have cytotoxic effects against different cancerous cell lines. However, their cytotoxicity against normal cells has been reported in some studies. Designing new temporin analogs with selective cytotoxicity against cancerous cell lines is considered a goal in drug development. In this regard, four new temporin-1CEa analogs (either C-terminally α-amidated or not) with increased net positive charge, as well as the potential of hydrogen bond formation were designed and their selective cytotoxicity against prostate carcinoma cell line (LNCaP) was evaluated. MTT assay was employed to test the simultaneous effects of the modifications on the cytotoxicity of the analogs against both normal (HFFF2) and cancerous (LNCaP) cell lines. Then, the in vitro selectivity index of each analog was determined using the equation of selectivity index (SI= IC50 of peptide against normal cell line / IC50 of peptide against cancerous cell line). The structural modifications of temporin-1CEa (increasing the net positive charge and removing C-terminally amidated group, as well as the potential of hydrogen bond formation on the non-polar face of α-helical structure) reduced the cytotoxicity of K2K3W15-COOH analog against both cancerous (LNCaP) and normal (HFFF2) cell lines. However, the modifications resulted in improving the in vitro selectivity index of K2K3W15-COOH compared to the temporin-1CEa (1.67 vs. 1.33, respectively). The results of the present study indicated that some structural modifications may lead to a diminution in the cytotoxicity of new analogs against cancerous cells. However, the same modifications can be associated with better selectivity indexes of new analogs due to a further decrease in their cytotoxicity against normal cells.

Liposome-encapsulated progesterone efficiently suppresses B-lineage cell proliferation

Progesterone suppresses several ancient pathways in a concentration-dependent manner. Based on these characteristics, progesterone is considered a candidate anticancer drug. However, the concentration of progesterone used for therapy should be higher than the physiological concentration, which makes it difficult to develop progesterone-based anticancer drugs. We previously developed liposome-encapsulated progesterone (Lipo-P4) with enhanced anticancer effects, which strongly suppressed triple-negative breast cancer cell proliferation in humanized mice. In this study, we aimed to clarify whether Lipo-P4 effectively suppresses the proliferation of B-lineage cancer cells. We selected six B-cell lymphoma and two myeloma cell lines, and analyzed their surface markers using flow cytometry. Next, we prepared liposome-encapsulated progesterone and examined its effect on cell proliferation in these B-lineage cancer cells, three ovarian clear cell carcinoma cell lines, two prostate carcinoma cell lines, and one triple-negative breast cancer adenocarcinoma cell line. Lipo-P4 suppressed the proliferation of all cancer cell lines. All B-lineage cell lines, except for the HT line, were more susceptible than the other cell types, regardless of the expression of differentiation markers. Empty liposomes did not suppress cell proliferation. These results suggest that progesterone encapsulated in liposomes efficiently inhibits the proliferation of B-lineage cells and may become an anticancer drug candidate for B-lineage cancers.

LC/MS/MS and GC/MS/MS metabolic profiling of Leontodon hispidulus, in vitro and in silico anticancer activity evaluation targeting hexokinase 2 enzyme

Leontodon hispidulus Boiss is a wild annual plant growing in Egypt. The present study aims for the first time, to evaluate the phytochemical profile of the main secondary metabolites of the optimized ethanolic extract of the plant using Quadrupole Time-of-Flight Liquid chromatography-mass spectrometry and Gas chromatography-mass spectrometry. It also aims to assess the anticancer activity of its different fractions against the prostate carcinoma cell line. Moreover, an in-silico docking study was performed using the Hexokinase-two enzyme. LC-qToF-MS analysis revealed the tentative identification of 36 phenolic compounds including the glycosides of (luteolin, quercetin, kaempferol, apigenin, isorhamnetin, and daidzein), coumarines (esculin, esculetin, and daphnetin), and phenolic acids (chlorogenic, caffeic, quinic, P-coumaric, and rosmarinic). GC–MS/MS analysis revealed the presence of 18 compounds where palmitic acid, myristic acid, alpha-amyrin, and beta-amyrin were the major ones. The cytotoxic activity results revealed that methylene chloride and ethyl acetate fractions showed the highest cytotoxic activity against the PC3 cell line, with IC50 values of 19, and 19.6 μg/ml, respectively. Interestingly, the docking study demonstrated that apigenin-7-O-glucoside, luteolin-7-O-glucoside, kaempferol-3-O-glucuronide, quercetin-4′-O-glucoside, esculin, rosmarinic acid, chlorogenic acid, and α-amyrin exhibited high affinity to the selected target, HEK-2 enzyme.

Abstract 2824: Establishing prostate cancer models for orthotopic and bone metastatic growth using the 22Rv1cell line

Abstract Prostate cancer is the second most common cancer in men with new cases diagnosed in 1.4 million men each year. Luckily the 5-year survival rates in developed countries are high reaching over 90%. However, approximately one third will develop a metastatic disease. In metastatic patients, prostate cancer almost always progresses despite the androgen deprivation therapy and is then referred to as “castration-resistant (mCRPC)”. Bone is involved in 80% of patients with metastasis, and the bone lesions are typically osteoblastic. The 22Rv1 human prostate carcinoma cell line is androgen sensitive and shown to express androgen receptor (AR). They also express low levels of prostate-specific membrane antigen (PSMA). The aim of this study was to establish orthotopic and intratibial preclinical in vivo prostate cancer models that can be used in drug development when targeting cancer cells and their local environment. Male athymic nude mice (5-6 weeks old) and NOG mice (over 20 weeks old) were used in the study. 2.5 × 105 22Rv1 cells (ATCC) were inoculated orthotopically into the prostate of NOG mice, and 5 × 105 cells were inoculated intratibially into the bone marrow cavity of athymic nude mice. Tumor growth was followed by PSA measurements every second week using Human PSA ELISA assay. In addition, in the intratibial model, tumor-induced bone changes were monitored by X-ray imaging of the hind limbs. Prostates and hind limbs were collected at sacrifice, fixed in 10% NBF, and processed to paraffin blocks for further histological analysis. Sections of prostate were stained with hematoxylin-eosin (HE) and AR. Tumor-bearing and contralateral (healthy) tibias were stained with HE - OrangeG, MGT, TRAP, and AR. The observed tumor take rate was 92% in the orthotopic and 100% in the intratibial models. Confirmed by IHC, tumors formed in both the orthotopic and intratibial models expressed AR. 22Rv1 cells formed osteoblastic - lytic mixed bone lesions in the intratibial model. Based on lesion areas, randomization of the tumor bearing mice in the intratibial model can be done after 2 weeks from cancer cell inoculation. Taken together, the 22Rv1 prostate cancer models are relatively fast growing, express AR and present good take rates. Furthermore, the intratibial model represents robust tumor-induced changes in bone with strong osteoblastic component. Thus, these models have several advantages in efficacy studies of novel drug candidates for prostate cancer. Citation Format: Justyna Zdrojewska, Katja Fagerlund, Jenni H. Mäki-Jouppila, Mari I. Suominen. Establishing prostate cancer models for orthotopic and bone metastatic growth using the 22Rv1cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2824.

State-of-the-art in transposable element modulation affected by drugs in malignant prostatic cancer cells.

Over recent years, the investigation of transposable elements (TEs) has granted researchers a deeper comprehension of their characteristics and functions, particularly regarding their significance in the mechanisms contributing to cancer development. This manuscript focuses on prostate carcinoma cell lines and offers a comprehensive review intended to scrutinize the associations and interactions between TEs and genes, as well as their response to treatment using various chemical drugs, emphasizing their involvement in cancer progression. We assembled a compendium of articles retrieved from the PubMed database to construct networks demonstrating correlations with genes and pharmaceuticals. In doing so, we linked the transposition of certain TE types to the expression of specific transcripts directly implicated in carcinogenesis. Additionally, we underline that treatment employing different drugs revealed unique patterns of TE reactivation. Our hypothesis gathers the current understanding and guides research toward evidence-based investigations, emphasizing the association between antiviral drugs, chemotherapy, and the reduced expression of TEs in patients affected by prostate cancer.

Cellular responses to silencing of PDIA3 (protein disulphide-isomerase A3): Effects on proliferation, migration, and genes in control of active vitamin D

The active form of vitamin D, 1,25-dihydroxyvitamin D3, is known to act via VDR (vitamin D receptor), affecting several physiological processes. In addition, PDIA3 (protein disulphide-isomerase A3) has been associated with some of the functions of 1,25-dihydroxyvitamin D3. In the present study we used siRNA-mediated silencing of PDIA3 in osteosarcoma and prostate carcinoma cell lines to examine the role(s) of PDIA3 for 1,25-dihydroxyvitamin D3-dependent responses. PDIA3 silencing affected VDR target genes and significantly altered the 1,25-dihydroxyvitamin D3-dependent induction of CYP24A1, essential for elimination of excess 1,25-dihydroxyvitamin D3. Also, PDIA3 silencing significantly altered migration and proliferation in prostate PC3 cells, independently of 1,25-dihydroxyvitamin D3. 1,25-Dihydroxyvitamin D3 increased thermostability of PDIA3 in cellular thermal shift assay, supporting functional interaction between PDIA3 and 1,25-dihydroxyvitamin D3-dependent pathways. In summary, our data link PDIA3 to 1,25-dihydroxyvitamin D3-mediated signalling, underline and extend its role in proliferation and reveal a novel function in maintenance of 1,25-dihydroxyvitamin D3 levels.

Pro-oncogene FBI-1 inhibits the ferroptosis of prostate carcinoma PC-3 cells via the microRNA-324-3p/GPX4 axis.

Ferroptosis has been characterized as non-apoptotic programmed cell death and is considered a novel strategy for antitumor treatment. The factor that binds to inducer of short transcripts-1 (FBI-1) is an important proto-oncogene playing multiple roles in human malignancies and the development of resistance to therapy. However, the roles of FBI-1 in ferroptosis of endocrine independent prostate carcinoma are still unknown. The results of this study showed that FBI-1 inhibited the ferroptosis of prostate carcinoma PC-3 cells (a typical endocrine-independent prostate carcinoma cell line) via the miR-324-3p/glutathione peroxidase 4 (miR-324-3p/GPX4) axis. Overexpression of FBI-1 enhanced the expression levels of GPX4. In contrast, knockdown of FBI-1 decreased the expression of GPX4 and induced the ferroptosis of PC-3 cells. The miR-324-3p decreased the expression of GPX4 by targeting the 3'-untranslated region of GPX4 to induce ferroptosis. Notably, FBI-1 increased the expression of GPX4 by repressing the levels of miR-324-3p. The transcription of miR-324-3p was mediated by specificity protein 1 (SP1), and FBI-1 repressed the expression of miR-324-3p by repressing the activation of SP1. In clinical specimens, the endogenous levels of FBI-1 were positively associated with Glutathione Peroxidase 4 (GPX4) and negatively related with the expression of miR-324-3p. Therefore, the results indicated that the miR-324-3p/GPX4 axis participates in the FBI-1-mediated ferroptosis of prostate carcinoma cells.

Anti-tumour effects of lapatinib on HER2-positive canine prostatic carcinoma cell lines.

Canine prostatic carcinoma (cPC) is a urogenital tumour with a poor prognosis, for which no effective treatment has been established. Recently, it has been shown that human epidermal growth factor receptor type 2 (HER2) is overexpressed in cPC cells; however, the efficacy of HER2-targeted therapy remains unclear. Investigate the anti-tumour effect of lapatinib on HER2-positive cPC cell lines. Two cell lines (muPC and bePC) were established from two dogs with cPC and the effects of lapatinib treatment on cell proliferation, apoptosis, and HER2 downstream signalling were investigated. Furthermore, muPC was used to generate tumour-bearing mice, and the anti-tumour effects of lapatinib were examined in vivo. Lapatinib treatment inhibited the proliferation and phosphorylation of Erk1/2 and Akt, which are downstream signals of HER2. Furthermore, the TUNEL assay showed that lapatinib induced apoptosis in both cell lines. The muPC-engrafted nude mouse model showed that lapatinib significantly inhibited tumour growth and increased the area of necrotic tumour tissue compared to the vehicle-treated groups. Lapatinib exerts anti-tumour effects on cPC cells by inhibiting HER-2 signalling.

Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.

Antioxidant, cytotoxicity, and anti-prostate carcinoma effects of CuO nanoparticles containing Thymus vulgaris

In this work, we have described the green supported of CuO NPs over Thymus vulgaris (CuNPs) as a reducing/stabilizing nanocomposite in alkaline medium. In the cellular and molecular part of the recent study, the treated cells with CuNPs were assessed to determine the cytotoxicity and anti-human prostate carcinoma properties on prostate carcinoma cell lines i.e., LNCaP clone FGC-Luc2, 22Rv1, and NCI-H660. The morphological and physicochemical features of the prepared nanocomposite were determined using several advanced techniques as Field Emission Scanning Electron Microscopes (FE-SEM), Ultraviolet–visible spectroscopy (UV-Vis), and fourier transform infrared spectroscopy (FTIR) studies. In the antioxidant test, the IC50 of CuNPs and butylated hydroxytoluene (BHT) against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals were 94 and 88 μg/mL, respectively. The IC50 of CuNPs were 191, 275, and 250 μg/mL against LNCaP clone FGC-Luc2, 22Rv1, and NCI-H660 cell lines, respectively. In conclusion, our data suggest that the malignant prostate cell lines viability decreased in the CuNPs presence.

The IGF-Independent Role of IRS-2 in the Secretion of MMP-9 Enhances the Growth of Prostate Carcinoma Cell Line PC3.

Insulin receptor substrate-2 (IRS-2), a substrate of the insulin-like growth factor (IGF)-I receptor, is highly expressed in the prostate cancer cell line, PC3. We recently demonstrated that extracellular signal-regulated kinase (Erk1/2), a kinase downstream of IGF signaling, is activated in PC3 cells under serum starvation, and this activation can be inhibited by IRS-2 knockdown. Here, we observed that adding an IGF-I-neutralizing antibody to the culture medium inhibited the activation of Erk1/2. Suppression of Erk1/2 in IRS-2 knockdown cells was restored by the addition of a PC3 serum-free conditioned medium. In contrast, the IRS-2-silenced PC3 conditioned medium could not restore Erk1/2 activation, suggesting that IRS-2 promotes the secretion of proteins that activate the IGF signaling pathway. Furthermore, gelatin zymography analysis of the conditioned medium showed that matrix metalloproteinase-9 (MMP-9) was secreted extracellularly in an IRS-2 dependent manner when PC3 was cultured under serum starvation conditions. Moreover, MMP-9 knockdown suppressed Erk1/2 activation, DNA synthesis, and migratory activity. The IRS-2 levels were positively correlated with Gleason grade in human prostate cancer tissues. These data suggest that highly expressed IRS-2 activates IGF signaling by enabling the secretion of MMP-9, which is associated with hyperproliferation and malignancy of prostate cancer cell line, PC3.

Metabolic profiling and cytotoxic activities of ethanol extract of Dypsis leptocheilos aerial parts and its green synthesized silver nanoparticles supported by network pharmacology analysis

Cancer, which is characterized by uncontrolled cell growth and division with loss of physiological functions. It is one of the most fatal diseases in the world. For thousands of years, natural treatments, particularly those made from natural products, have been used to cure a variety of diseases, including cancer. Several Arecaceae species have been suggested as potential treatments for a range of cancer types. Arecaceae have a long history of use in folk medicine to treat tumors and a variety of infectious disorders. The green synthesis of silver nanoparticles (SNP) using the total ethanolic extract of Dypsis leptocheilos aerial parts (TEEDL) as a reducing agent was investigated for their cytotoxic activity (using the MTT assay) for the first time. A color change from faint yellow to reddish brown in the first stages of SNP synthesis, indicating the synthesis of nanoparticles. The prepared nanoparticles were also elucidated by using UV-visible spectroscopy, Fourier Transforms infrared spectroscopy (FT-IR), transmission electron microscope (TEM), and Zeta potential. The purified silver nanoparticle preparation demonstrated more promising cytotoxic activity against tested various cell lines than TEEDL. Cell viability by using the MTT assay demonstrated the cytotoxic activity of (TEEDL-based SNPs) against breast cancer cells (MCF-7), liver carcinoma (HepG2), colon carcinoma (HCT-116), and prostate carcinoma (PC-3) cell lines with IC50 = 4.49 ± 0.23, 0.95 ± 0.05, 1.8 ± 0.1, and 2.74 ± 0.52 µg/mL, respectively. To find out which of the secondary metabolites are responsible for this activity, the metabolic profile of TEEDL was investigated. It detected 29 compounds. Finally, a network pharmacology analysis was conducted to find out the annotated genes identified by the major identified flavonoidal compounds. The results identified 145 genes annotated by the 10 major flavonoidal compounds. AKR1B1and CA7 were highly represented genes. Four-gene disease networks were constructed; (gene-breast cancers), (gene-liver cancers), and (gene-colon cancers), and (gene-prostate cancers). KEGG pathway analysis showed the top biological pathways related to all genes were nitrogen metabolism pathway, the VEGF signaling pathway, and EGFR tyrosine kinase inhibitor resistance.

Stromal-epithelial interaction induces GALNT14 in prostate carcinoma cells.

Cell-cell communication is an important process in healthy tissue but also gains enhanced attention regarding pathological tissue. To date, the tumor microenvironment is gradually brought into focus when studying tumorigenesis. In the prostate gland, stromal and epithelial cells greatly interact to maintain homeostasis or tissue integrity. This study focuses on an indirect communication via soluble factors. To investigate the cell-cell interaction via soluble factors, the prostate carcinoma cell line LNCaP and the stromal primary cells p21 were co-cultured without direct contact and RNA was isolated at defined time points. Differences in gene expression were finally analyzed by RNA sequencing. RNA sequencing revealed a time-depending differential expression profile. Selected factors were subsequently characterized at molecular level and analyzed in human prostate tissue of different developmental stages as well as pathology. GALNT14 was one of the highest induced co-culture-specific genes in LNCaP cells. Detection in healthy tissue and BPH revealed an age-dependent decrease in GALNT14 expression. Moreover, in prostate carcinoma, GALNT14 expression heavily varied independent of the Gleason score. Overall, this work provides a basis for further studies related to paracrine stromal-epithelial interaction in prostate carcinoma and highlights the importance of GALNT14.

Bioinspired thiazolo-[2,3-b] quinazolin-6-one derivatives as potent anti-cancer agents targeting EGFR: their biological evaluations and in silico assessment.

Cancer is a challenging and second most deadly disease. The epidermal growth factor receptors (EGFRs) dimerize upon ligand bindings to the extracellular domain that intiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphrylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. In this study, we unravel the binding mechanism of newly synthesized thiazolo-[2,3-b] quinazolin-6-one and evaluate their anti-cancer activity against ovary and prostate carcinoma cell lines (OVCAR-3 and PC-3). Synthesized molecules exhibited promising anti-cancer activity against OVCAR-3 and PC-3 carcinoma cell lines with inhibitory concentrations ranging from 13.4 ± 0.43 to 23.6 ± 1.22μM and 7.5 ± 0.62 to 67.5 ± 1.24μM, respectively. These compounds induced apoptosis and resulted in cell cycle arrest at G1 and G2/M transition phases. Next, the nude mice models were taken to investigate the toxicity of the 4bi compound, and in vivo investigations revealed no effects upon examined organs (liver and kidney) treated at different concentrations. Moreover, the combined in silico approaches, molecular docking, molecular dynamics simulations, and MM/PBSA methods were performed to assess the binding affinity and stability of bioinspired synthesized congeners with the epidermal growth factor receptor tyrosine kinase (EGFR-TK). The free binding energy (ΔGbind) of the 4bi molecule was found comparable to Erlotinib drug. The test molecule could be competent for further usage to determine its efficicacy in cancer therapeutics.

Modifications in cellular viability, DNA damage and stress responses inflicted in cancer cells by copper-64 ions.

Due to combined therapeutical emissions, a high linear energy transfer Auger-electrons with the longer ranged β- particles, 64Cu-based radiopharmaceuticals raise particular theragnostic interest in cancer, by joined therapeutic and real-time PET imaging properties. The in vitro study aimed to investigate the biological and molecular background of 64CuCl2 therapy by analyzing the damages and stress responses inflicted in various human normal and tumor cell lines. Colon (HT29 and HCT116) and prostate carcinoma (DU145) cell lines, as well as human normal BJ fibroblasts, were treated up to 72 h with 2-40 MBq/mL 64CuCl2. Radioisotope uptake and retention were assessed, and cell viability/death, DNA damage, oxidative stress, and the expression of 84 stress genes were investigated at various time points after [64Cu]CuCl2 addition. All the investigated cells incorporated 64Cu ions similarly, independent of their tumoral or normal status, but their fate after exposure to [64Cu]CuCl2 was cell-dependent. The most striking cytotoxic effects of the radioisotope were registered in colon carcinoma HCT116 cells, for which a substantial decrease in the number of metabolically active cells, and an increased DNA damage and oxidative stress were registered. The stress gene expression study highlighted the activation of both death and repair mechanisms in these cells, related to extrinsic apoptosis, necrosis/necroptosis or autophagy, and cell cycle arrest, nucleotide excision repair, antioxidant, and hypoxic responses, respectively. The in vitro study indicated that 40 MBq/mL [64Cu]CuCl2 delivers a therapeutic effect in human colon carcinoma, but its use is limited by harmful, yet lower effects on normal fibroblasts. The exposure of tumor cells to 20 MBq/mL [64Cu]CuCl2, might be used for a softer approach aiming for a lower radiotoxicity in normal fibroblasts as compared to tumor cells. This radioactive concentration was able to induce a persistent decrease in the number of metabolically active cells, accompanied by DNA damage and oxidative stress, associated with significant changes in stress gene expression in HCT116 colon cancer cells.

Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) protein tyrosine kinases co-expressed in various cancers such as ovarian, breast, colon, and prostate subtypes. Herein, new TAK-285 derivatives (9a–h) were synthesised, characterised, and biologically evaluated as dual EGFR/HER2 inhibitors. Compound 9f exhibited IC50 values of 2.3 nM over EGFR and 234 nM over HER2, which is 38-fold of staurosporine and 10-fold of TAK-285 over EGFR. Compound 9f also showed high selectivity profile when tested over a small kinase panel. Compounds 9a–h showed IC50 values in the range of 1.0–7.3 nM and 0.8–2.8 nM against PC3 and 22RV1 prostate carcinoma cell lines, respectively. Cell cycle analysis, apoptotic induction, molecular docking, dynamics, and MM-GBSA studies confirmed the plausible mechanism(s) of compound 9f as a potent EGFR/HER2 dual inhibitor with an effective antiproliferative action against prostate carcinoma.