Apoptosis In DU145 Research Articles

Dihydroartemisinin Modulates Prostate Cancer Progression by Regulating Multiple Genes via the Transcription Factor NR2F2.

This study aimed to investigate the effect of dihydroartemisinin (DHA) on DU145 cells and the role of NR2F2 (COUP-TFII) and its potential target genes in this process. GSE122625 was used to identify differentially expressed genes (DEGs) between the DHA-treated and control groups. Protein-protein interaction (PPI) network analysis was performed to identify hub genes, and the ChEA3 database was used to identify potential transcription factors. qRT-PCR and Western blot were used to validate the expression of genes of interest and functional assays were performed to evaluate the effect of DHA on DU145 and PC-3 cells. To solidify the regulatory relationship of NR2F2 with EFNB2, EBF1, ETS1, and VEGFA, a Chromatin Immunoprecipitation (ChIP) experiment was performed. We identified 85 DEGs in DU145 cells treated with DHA, and PPI network analysis identified NR2F2 as a hub gene and potential transcription factor. The regulatory network of NR2F2 and its potential target genes (EFNB2, EBF1, ETS1, and VEGFA) was constructed, and the expression of these genes was upregulated in DHA-treated cells compared to control cells. Functional assays showed that DHA treatment inhibited epithelial-mesenchymal transition, reduced inflammation, and promoted apoptosis in DU145 and PC-3 cells. Furthermore, NR2F2 knockdown receded the DHA-induced upregulation of target genes and functional changes of DU145 and PC-3 cells. The outcomes of ChIP unequivocally pointed to a positive regulatory role of NR2F2 in these gene expressions. Our study suggests that DHA treatment affects the functions of DU145 and PC-3 cells by regulating the expression of NR2F2 and its potential target genes, and NR2F2 may serve as a potential therapeutic target for prostate cancer.

Raltitrexed induces apoptosis through activating ROS-mediated ER stress by impeding HSPA8 expression in prostate cancer cells

Prostate cancer is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC). CRPC metastasis is the main reason for its high mortality rate. At present, it lacks effective treatment for patients with CRPC. Raltitrexed (RTX) has been shown to be effective in the treatment of colorectal cancer. However, the effect of RTX on prostate cancer and the underlying mechanism remain unknown. In the current study, we found that RTX could dose-dependently inhibit proliferation, migration, colony formation and induce apoptosis in DU145 and PC-3 cells. RTX also increased ROS generation in prostate cancer cells. Pretreatment with N-acetyl-L-cysteine (NAC) significantly prevented RTX-induced cell apoptosis and endoplasmic reticulum (ER) stress signaling activation in prostate cancer cells. Additionally, we found RTX-induced ROS generation and ER stress activation depended on the expression of heat shock protein family A member 8 (HSPA8). Over-expression of HSPA8 could alleviate RTX-induced cell apoptosis, ROS generation and ER stress signaling activation. Finally, our study also showed that RTX attenuated the tumor growth of prostate cancer in the DU145 xenograft model and significantly downregulated HSPA8 expression and activated ER stress signaling pathway in tumor tissues. Our study is the first to reveal that RTX induces prostate cancer cells apoptosis through inhibiting the expression of HSPA8 and further inducing ROS-mediated ER stress pathway action. This study suggests that RTX may be a novel promising candidate drug for prostate cancer therapy.

Serine/threonine kinase 36 induced epithelial-mesenchymal transition promotes docetaxel resistance in prostate cancer

To investigate the role and potential mechanism of serine/threonine kinase 36 (STK36) in docetaxel resistance-prostate cancer (PCa). The expression of STK36 in PCa and the correlation with clinicopathological characteristics of PCa patients were analyzed using the data from different databases and tissue microarrays. To investigate the role of STK36 on cell proliferation, invasion, and migration, STK36 was overexpressed and silenced in DU-145 and PC-3 cell lines. Cell counting kit-8 (CCK8) was used to test cell proliferation. Cell invasion and migration were detected by cell wound scratch assay and trans well, respectively. The expression profile of STK36, E-Cadherin, and Vimentin was analyzed by Western blot. Cell apoptosis was detected by the TUNEL assay. STK36 expression was upregulated in PCa tissue compared with adjacent benign PCa tissue; it was higher in patients with advanced stages compared with lower stages and was significantly correlated with decreased overall survival. Up-regulation of STK36 significantly promoted the proliferation, invasion, and migration of DU-145 and PC-3 cells and compensated for the suppression caused by docetaxel treatment in vitro. A striking apoptosis inhibition could be observed when dealing with docetaxel, although the apoptosis of DU-145 and PC-3 cells was not affected by the STK36 exclusive overexpression. Besides, E-Cadherin expression was restrained while the expression levels of vimentin were all enhanced. The knockdown of STK36 reversed the above process. STK36 up-regulation could accelerate the biological behavior and docetaxel resistance of PCa by epithelial-mesenchymal transition (EMT) activation. STK36 may be potentially used as a target in PCa resolvent with docetaxel.

ULTRASOUND-ASSISTED SYNTHESIS AND DOCKING STUDY OF NOVEL CHROMONE-THIADIAZOLE INTEGRATED PHOSPHONATE DERIVATIVES TARGETING TOPOISOMERASE II AS ANTICANCER AGENTS

Objective: The present studies discuss the anticancer activity of different topoisomerase II inhibitors with docking study.
 Methods: The work reports the synthesis of novel diethyl (4-oxo-4H-chromen-3-yl)(5-substituted phenyl-1,3,4-thiadiazol-2-ylamino)methyl phosphonate derivatives 6(a-j). They were synthesized through one-pot three-component Kabachnik-Fields reaction by using ultrasonicator processor, at room temperature in presence of Zirconium oxychloride (ZrOCl2).
 Results: The structures of the synthesized compounds were confirmed by spectral analysis. The synthesized derivatives 6(a-j) were evaluated for their in vitro anticancer activity against human cancer cell lines such as DU 145 (Human Prostate Cancer) and MCF-7 (Breast cancer) and also on non-tumor cell lines such as MCF-10 (normal breast epithelial cell) by MTT assay. From the anticancer screening results data, compound 6e was found to be the most potent anticancer compound among the synthesized compounds against MCF-7 and DU 145 cancer cell lines with IC50 value of 2.97 µM and 3.11 µM, respectively. The compound 6h has shown cell cycle arrest at G2/M phase, along with the decrease of cells at G0/G1 phage. The compound 6h was able to induce apoptosis in DU 145 cell lines. The synthesized compounds 6(a-j) were further evaluated for their topoisomerase II inhibitory activity.
 Conclusion: The anticancer screening result and MTT assay, along with the docking study shows that the synthesised derivative are active anticancer agent against MCF-10, DU-145 and MCF-7 cell line.

Apoptosis induction in human prostate cancer cells related to the fatty acid metabolism by wogonin-mediated regulation of the AKT-SREBP1-FASN signaling network.

Prostate cancer (PCa) cells exploit cellular metabolic reprogramming as their survival advantage, especially aberrant lipid signaling and metabolism. Although recent studies deemed that PCa tends to rely on lipid fuel in comparison with aerobic glycolysis, the relationship between lipid metabolism and cancer growth remains unknown. We demonstrated that wogonin, a naturally occurring mono-flavonoid, could induce apoptosis of PCa cells in vivo and in vitro. Mechanistically, 100μM wogonin significantly increased the expression of proteins related to the fatty acid synthesis and accumulation as a result of stimulation of AKT phosphorylation and nuclear accumulation of sterol regulatory element-binding protein 1 (SREBP1). The wogonin-induced up-regulation of fatty acid synthase (FASN) promoted fatty acid synthesis and storage, while increased oxidation in mitochondria driven by carnitine palmitoyl-transferase 1A (CPT1A) resulted in the loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation, ultimately inducing apoptosis in DU145 and 22Rv1 cells. In vivo, 100mg/kg of wogonin (i.v.) significantly repressed tumor growth without any obvious toxicity in the PCa xenograft model. In short, we proved that wogonin regulated the fatty acid metabolism and induced apoptosis by activating the AKT-SREBP1-FASN signaling network in human PCa cells, and it exhibited potent anti-tumor effects both in vivo and vitro. Thus it might be a promising candidate for the development of anti-cancer drugs.

MiR-31-3p functions as a tumor suppressor by directly targeting GABBR2 in prostate cancer.

MicroRNAs are key regulators of gene expression in tumorigenesis. In this study, we investigated the tumor-suppressive function of miR-31-3p. Analysis of the Gene Expression Omnibus database revealed that the expression of miR-31-3p in prostate cancer tissues is lower than that in adjacent normal tissues from patients with prostate cancer. Moreover, miR-31-3p induces apoptosis in DU145, PC-3, and LNCap prostate cancer cells, while those transfected with miR-31-3p exhibit significantly decreased cell proliferation, migration, invasiveness, and tumor sphere-forming ability, as determined using the cell counting kit-8, transwell, and sphere-forming assays. Further analysis revealed that GABBR2 is a direct target of miR-31-3p. Within a DU145 xenograft murine model, intratumoral injection of a miR-31-3p mimic suppresses tumor growth. Taken together, the findings of this study suggest that miR-31-3p performs a novel tumor-suppressive function in prostate cancer and may represent a novel target for anti-prostate cancer miRNA therapeutics.

Antimicrobial, antibiofilm, and anticancer potential of silver nanoparticles synthesized using pigment-producing Micromonospora sp. SH121

Silver nanoparticles (AgNPs) have gained interest as an alternative pharmaceutical agent because of antimicrobial resistance and drug toxicity. Considering the increasing request, eco-friendly, sustainable, and cost-effective synthesis of versatile AgNPs has become necessary. In this study, green-made AgNPs were successfully synthesized using Micromonospora sp. SH121 (Mm-AgNPs). Synthesis was verified by surface plasmon resonance (SPR) peak at 402 nm wavelength in the UV-Visible (UV-Vis) absorption spectrum. Scanning electron microscopy (SEM) analysis depicted that Mm-AgNPs were in the size range of 10–30 nm and spherical. Fourier transform infrared spectroscopy (FTIR) confirmed the existence of bioactive molecules on the surface of nanoparticles. The X-ray diffraction (XRD) analysis revealed the face-centered cubic (fcc) structure of the Mm-AgNPs. Their polydispersity index (PDI) and zeta potential were 0. 284 and −35.3 mV, respectively. Mm-AgNPs (4–32 µg/mL) exhibited strong antimicrobial activity against Bacillus cereus, Enterococcus faecalis, Enterococcus hirae, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas putida, Staphylococcus epidermidis, Streptococcus pneumoniae, and Aspergillus flavus. Mm-AgNPs partially inhibited the biofilm formation in Acinetobacter baumannii, E. coli, K. pneumoniae, and Pseudomonas aeruginosa. Furthermore, results showed that low concentrations of Mm-AgNPs (1 and 10 µg/mL) caused higher cytotoxicity and apoptosis in DU 145 cells than human fibroblast cells. Based on the results, Mm-AgNPs have an excellent potential for treating infectious diseases and prostate cancer.

Functional and mutational analysis after radiation and cetuximab treatment on prostate carcinoma cell line DU145

BackgroundEpidermal Growth Factor Receptor is often overexpressed in advanced prostate carcinoma. In-vitro-studies in prostate carcinoma cell line DU145 have demonstrated increased sensibility to radiation after cetuximab treatment, but clinical data are not sufficient to date.MethodsWe analyzed effects of radiation and cetuximab in DU145 and A431 using proliferation, colony-forming-unit- and annexin-V-apoptosis-assays. Changes in protein expression of pEGFR and pERK1/2 after radiation and cetuximab treatment were analyzed. Using NGS we also investigated the impact of cetuximab long-term treatment.ResultsCell counts in DU145 were reduced by 44% after 4 Gy (p = 0.006) and 55% after 4 Gy and cetuximab (p < 0.001). The surviving fraction (SF) was 0.69 after 2 Gy, 0.41 after 4 Gy and 0.15 after 6 Gy (each p < 0.001). Cetuximab treatment did not alter significantly growth reduction in 4 Gy radiated DU145 cells, p > 0.05 or SF, p > 0.05, but minor effects on apoptotic cell fraction in DU145 were detected. Using western blot, there were no detectable pEGFR and pERK1/2 protein signals after cetuximab treatment. No RAS mutation or HER2 amplification was detected, however a TP53 gen-mutation c.820G > T was found.ConclusionsRadiation inhibits cell-proliferation and colony-growth and induces apoptosis in DU145. Despite blocking MAP-Kinase-pathway using cetuximab, no significant radiation-sensitizing-effect was detected. Cetuximab treatment did not induce resistance-mutations. Further research must clarify which combination of anti-EGFR treatment strategies can increase radiation-sensitizing-effects.

Hispidulin inhibits proliferation, migration, and invasion by promoting autophagy via regulation of PPARγ activation in prostate cancer cells and xenograft models.

Prostate cancer (PCa) is one of the important factors of cancer deaths especially in the western countries. Hispidulin (4',5,7-trihydroxy-6-methoxyflavone) is a phenolic flavonoid compound proved to possess anticancer properties, but its effects on PCa are left to be released. The aims of this study were to investigate the effects and the relative mechanisms of Hispidulin on PCa development. Hispidulin administration inhibited proliferation, invasion, and migration, while accelerated apoptosis in Du145 and VCaP cells, which was accompanied by PPARγ activation and autophagy enhancement. The beneficial effects of Hispidulin could be diminished by PPARγ inhibition. Besides, Hispidulin administration suppressed PCa tumorigenicity in Xenograft models, indicating the anticancer properties in vivo. Therefore, our work revealed that the anticancer properties of Hispidulin might be conferred by its activation on PPARγ and autophagy.

Downregulation of CDCA5 Can Inhibit Cell Proliferation, Migration, and Invasion, and Induce Apoptosis of Prostate Cancer Cells.

Prostate cancer (PC) is the most common form of cancer in males and accounts for many cancer-related deaths. Human cell division cycle associated 5 (CDCA5) may be a useful marker for predicting tumor metastasis and therapeutic target for the treatment of PC patients. In this study, we investigated the role of CDCA5 in prostate cancer progression. Immunohistochemistry was performed on 20 prostate cancer tissue samples. We performed immunohistochemistry on 20 prostate cancer tissue samples. CDCA5, a gene that is differentially expressed in prostate cancer, was screened with The Cancer Genome Atlas database. In both DU145 and PC-3 cells, CDCA5 levels consistently affected cell proliferation, colony formation, apoptosis, migration, and invasion. CDCA5 knockdown significantly inhibited PC cell proliferation, migration, and invasion. Furthermore, the apoptosis of DU145 and PC-3 cells was significantly increased after CDCA5 downregulation. Further investigations revealed that CDCA5 may participate in the development of PC through interaction with TWIST1, CDH1, and CDH2. The present results provide a novel insight into the important and multifaceted role of CDCA5 in PC, indicating that CDCA5 is a promising biomarker and therapeutic target for PC.

Synthesis and biological evaluation of Schizandrin derivatives as tubulin polymerization inhibitors

A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Particularly, 4a and 4b demonstrated potent activity against DU-145 and RKOP3 cell lines with IC50 values of 3.42 µM and 3.35 µM respectively. To characterize the molecular mechanisms involved in antitumoral activity, these two compounds, 4a and 4b were selected for further studies. Cell cycle analysis revealed that both the compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase. To know the extent of apoptosis in DU145 and RKOP3 cell lines, Annexin V-FITC were performed. Moreover, the tubulin polymerization assay indicated that 4a and 4b exhibits potent inhibitory effect on the tubulin assembly. Molecular docking studies and competitive binding assay also indicated that 4a and 4b effectively bind at the colchicine binding site of the tubulin.

Ruthenium (II) complexes with N, O-chelating proline and threonine ligands cause selective cytotoxicity by the induction of genomic instability, cell cycle arrest and apoptosis in breast and prostate tumor cells

Ruthenium complexes are being considered as novel chemotherapeutic alternatives for cancer treatment. In our study, we assessed the antitumoral activities of novel ruthenium complexes coupled to the amino acids proline (RuPro) and threonine (RuThr) in prostate tumor cell lines (DU145) and breast (MCF7), and normal cell lines of the lung fibroblast (GM07492A). Our results revealed that the EC50 of the complexes for DU145 and MCF7 was two times lower than that GM07492A. Moreover, RuPro and RuThr were not able to induce significant genomic instability, cell cycle arrest or cell death in GM07492A, but could induce DNA damage, arrest in G2/M and apoptosis in DU145 and MCF7. Furthermore, BAX, TP53 and ATM were found to be upregulated in DU145 and MCF7 treated with RuPro and RuThr, in which, a higher ASCT2 gene expression was also observed. Using molecular docking, RuPro and RuThr interact with ASCT2, suggesting that this transporter might have a pivotal role in the execution of their activities. Hence, our results with RuPro and RuThr are capable of selectively inducing genetic damage, cell cycle arrest and apoptosis in DU145 and MCF7. We suggest that the selective action of the RuPro and RuThr complexes is related to the higher expression of ASCT2 in the tumor cells.

Abstract 2495: Glucosamine enhances TRAIL-induces apoptosis in DU145 and Hela cancer cell lines

Abstract Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has attracted wide attention and extensive research because of selective apoptosis of tumor cells but not of normal cells. However, the clinical trials using TRAIL alone were disappointed due to the resistance of cancer cells to the TRAIL-treatment. Several resistant mechanisms, such as low expression of death receptors, and overexpression of cFLIP, BCL-2 antiapoptotic family members and XIAP were proposed. Tunicamycin was reported to enhance the expression of death receptor 5 through the activation of CHOP. Similar to tunicamycin, glucosamine is known to increase the expression of CHOP by inducing ER stress. We thus investigated whether glucosamine could increase the expression of death receptor 5 to overcome TRAIL-resistance. We found that glucosamine treatment of DU145 cells did not increase the expression of death receptor 5 on the cell surface, even though the overall expression was increased. However, glucosamine significantly increased TRAIL-induced apoptosis in DU145 and Hela cells. Our investigation revealed that glucosamine sensitized cancer cells to TRAIL-induced apoptosis through both intrinsic and extrinsic apoptosis pathways, as evidenced by the cleavage of both caspase 9 and caspase 8. Our data further showed that the combination of TRAIL with glucosamine suppressed the expression of cFLIP, BCL-2 and XIAP, translocated BAK to the mitochondrial outer membrane, and released cytochrome C and SMAC from mitochondrial. Interestingly, in addition to the activation of apoptotic pathways, TRAIL-mediated inflammatory responses were attenuated by glucosamine treatment. Pretreatment of glucosamine reduced the TRAIL-induced nuclear NF-kB level and the expression of IL-6 and IL-8. Together, these results demonstrated that the combination treatment, TRAIL with glucosamine, may provide a promising novel strategy for treating different human cancers by overcoming TRAIL-resistance and inhibiting TRAIL-induced inflammation. Citation Format: Chao Sun, Viktor Chesnokov, Keiichi Itakura. Glucosamine enhances TRAIL-induces apoptosis in DU145 and Hela cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2495.

CID-6033590 inhibits p38MAPK pathway and induces S-phase cell cycle arrest and apoptosis in DU145 and PC-3 cells

Metastatic prostate cancer, with no effective treatment, is among the leading causes of cancer-associated deaths in men. Overexpression of p38αMAPK has been observed in neuroendocrine prostate cancer patients and in both DU145 and PC-3 cell lines and represents a good drug target. Sulfonamide derivatives have shown biological activities against many human diseases, including cancer. CID-6033590, a sulfonylhydrazide compound, screened from PubChem database by molecular docking with p38αMAPK, was evaluated for anti-cancerous activities. CID-6033590 induced toxicity in both DU145 and PC-3 cells in a concentration and time-dependent manner with an IC50 value of 60 μM and 66 μM, respectively. Sub-cytotoxic concentrations of the compound significantly induced S-phase cell cycle arrest, inhibited cyclinA/CDK2 complex and blocked cell proliferation. Further, CID-6033590 downregulated phosphorylation of p38MAPK (P-p38) as well as its downstream targets, Activating transcription factor 2 (ATF-2) and Heat shock protein 27 (Hsp27). The compound increased ROS and decreased mitochondrial membrane potential (Δψm), downregulated Bcl-2 and survivin and cleaved poly ADP ribose polymerase (PARP) and caspase-3, indicating the induction of apoptosis. The evaluaion of the compound on noncancerous, human prostatic epithelial cell line RWPE-1, and healthy murine tissues yielded no significant toxicity. Taken together, we suggest CID-6033590 as a potential candidate for prostate cancer therapy.

MALAT1 silencing suppresses prostate cancer progression by upregulating miR-1 and downregulating KRAS.

BackgroundProstate cancer (PC) is the second leading cause of cancer-related deaths among men. Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) performed as an oncogene in multiple cancers including PC. However, the molecular mechanisms of MALAT1 implicated in PC progression have not been thoroughly elaborated.Materials and methodsReverse transcription-quantitative polymerase chain reaction assay was used to detect the expressions of MALAT1 and microRNA-1 (miR-1). Protein levels of cleaved poly (ADP-ribose) polymerase, cleaved caspase-3, BAX, bcl-2, and KRAS were determined using a western blot assay. Cell proliferation was assessed by colony formation and MTS assays. Cell migration capacity was examined by transwell migration assay (Corning Incorporated, Corning, NY, USA). Apoptosis rate was measured by flow cytometry via double staining of annexin V-FITC and propidium iodide. Luciferase and RNA immunoprecipitation assays were employed to explore the relationship among miR-1, MALAT1, and KRAS.ResultsMALAT1 expression was upregulated and miR-1 expression was downregulated in PC tissues and cell lines. MALAT1 knockdown inhibited cell proliferation and migration, and promoted cell apoptosis in androgen receptor-negative DU145 and PC3 cells. Molecular mechanism explorations disclosed that MALAT1 acted as a molecular sponge of miR-1 in DU145 cells. Moreover, miR-1 downregulation partly abrogated MALAT1 silencing-mediated anti-proliferative, antimigratory, and proapoptotic effects in DU145 and PC3 cells. Further investigation revealed that KRAS was a target of miR-1 in DU145 cells. MALAT1 acted as a competing endogenous RNA of miR-1, resulting in the increase of KRAS expression in DU145 and PC3 cells. Furthermore, miR-1 overexpression hampered proliferation and migration and promoted apoptosis in DU145 and PC3 cells, while these effects were markedly weakened following KRAS upregulation.ConclusionMALAT1 knockdown inhibited proliferation and migration and facilitated apoptosis by upregulating miR-1 and downregulating KRAS in androgen receptor-negative PCa cells, providing a new insight into the molecular basis of MALAT1 and a potential biomarker or therapeutic target for suppressing castration-resistant PC.

Plumbagin Triggers ER Stress-Mediated Apoptosis in Prostate Cancer Cells via Induction of ROS

Background/Aims: Prostate cancer (PCa) is the second most frequently diagnosed cancer in men worldwide. Currently available therapies for hormone-refractory PCa are only marginally effective. Plumbagin (PLB), a natural naphthoquinone isolated from the traditional folk medicine Plumbago zeylanica, is known to selectively kill tumor cells. Nevertheless, antitumor mechanisms initiated by PLB in cancer cells have not been fully defined. Methods: MTT assay was used to evaluate the effect of PLB on the viability of cancer cells. Cell apoptosis and reactive oxygen species (ROS) production were determined by flow cytometry. Protein expression was detected by western blotting. In vivo anti-tumor effect was measured by using tumor xenoqraft model in nude mice. Results: In the present study, we found that PLB decreases cancer cell growth and induces apoptosis in DU145 and PC-3 cells. In addition, by increasing intracellular ROS levels, PLB induced a lethal endoplasmic reticulum stress response in PCa cells. Importantly, blockage of ROS production significantly reversed PLB-induced ER stress activation and cell apoptosis. In vivo, we found that PLB inhibits the growth of PCa xenografts without exhibiting toxicity Treatment of mice bearing human PCa xenografts with PLB was also associated with induction of ER stress activation. Conclusion: Inducing ER stress by PLB thus discloses a previously unrecognized mechanism underlying the biological activity of PLB and provides an in-depth insight into the action of PLB in the treatment of hormone-refractory PCa.

Design, synthesis and biological evaluation of new β-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors

A series of new β-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 μM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV–Visible, fluorescence, circular dichroism and molecular docking studies revealed that the β-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.

Two novel peptides derived from Sinonovaculaconstricta inhibit the proliferation and induce apoptosis of human prostate cancer cells.

In China, the incidence of prostate cancer has been increasing. Toxicity, drug resistance and limited transient benefits in patients are the main problems associated with standard chemotherapeutic regimens, and new drugs are therefore required to treat prostate cancer. SCH-P9 and SCH-P10 proteins were obtained from Sinonovacula constricta hydrolysates. The amino acid sequences of SCH-P9 and SCH-P10 were identified as Leu-Pro-Gly-Pro and Asp-Tyr-Val-Pro, with molecular weights of 382.46 Da and 492.53 Da, respectively. An MTT assay, annexin V-fluorescein isothiocyanate (FITC) staining and cell cycle analysis were applied to identify the viability of cells, stages of apoptosis, and cell cycle distribution, respectively. SCH-P9 and SCH-P10 inhibited the growth of DU-145 and PC-3 cells in a dose- and time-dependent manner. Annexin V-FITC staining and flow cytometry analysis were employed to measure apoptosis and cell cycle arrest, respectively. SCH-P9 and SCH-P10 inhibited the growth of DU-145 cells by reducing the number of cells in G0/G1 phase, increasing the number in subG1 phase and inducing apoptosis. SCH-P9 reduced the number of PC-3 cells in subG1 and G0/G1 phases, increased the number of cells in G2/M phase and induced apoptosis. SCH-P10 reduced the number of PC-3 cells in G2/M phase, increased the number of cells in G0/G1 phase and induced apoptosis. In conclusion, the results demonstrated that SCH-P9 and SCH-P10 induced apoptosis in DU-145 and PC-3 cells and may, therefore, exhibit potential for application in the treatment of prostate cancer.

RLIP76-dependent suppression of PI3K/AKT/Bcl-2 pathway by miR-101 induces apoptosis in prostate cancer

MicroRNA-101 (miR-101) participates in carcinogenesis and tumor progression in various cancers. However, its biological functions in prostate cancer are still unclear. Here, we demonstrate that miR-101 represents a critical role in regulating cell apoptosis in prostate cancer cells. We first demonstrated that miR-101 treatment promoted apoptosis in DU145 and PC3 cells by using flow cytometric analysis and transmission electron microscopy (TEM). To verify the mechanisms, we identified a novel miR-101 target, Ral binding protein 1 (RLIP76). We found miR-101 transfection significantly suppresses RLIP76 expression, which can transactivate phosphorylation of PI3K-Akt signaling, and resulted in an amplification of Bcl2-induced apoptosis. Furthermore, we demonstrated that RLIP76 overexpression could reverse the anti-tumor effects of miR-101 in DU145 and PC3 cells by using flow cytometry assay and MTT assay. Taken together, our results revealed that the effect of miR-101 on prostate cancer cell apoptosis was due to RLIP76 regulation of the PI3K/Akt/Bcl-2 signaling pathway.

Upregulation of death receptor 5 and activation of caspase 8/3 play a critical role in ergosterol peroxide induced apoptosis in DU 145 prostate cancer cells.

BackgroundThough ergosterol peroxide (EP) derived from Neungyi mushrooms (Sarcodon aspratus) was known to have cytotoxic, apoptotic, anti-inflammatory and antimycobacterial effects, the underlying molecular mechanism of EP still remains unclear. Thus, in the present study, the apoptotic mechanism of EP was elucidated in DU 145 prostate cancer cells.MethodsCell viability of prostate cancer cells was measured by MTT assay. To see whether EP induces the apoptosis, FACS, western blot and TUNEL assay were performed. To determine the role of Death receptor (DR) 5 molecules in EP-induced apoptosis in DU 145 prostate cancer cells, the silencing of DR 5 was performed by using siRNAs.ResultsEP showed significant cytotoxicity against DU 145, PC 3, M2182 prostate cancer cells. Also, EP effectively increased the sub G1 population and terminal deoxynucleotidyl transferase DUTP nick end labeling (TUNEL) positive cells in DU 145 prostate cancer cells. Furthermore, western blotting revealed that EP cleaved poly (ADP-ribose) polymerase (PARP) and caspase 8/3, attenuated the expression of fluorescence loss in photobleaching (FLIP), Bcl-XL and Bcl-2 as well as activated Bax, Fas-associated death domain (FADD) and DR 5 in a concentration dependent manner in DU 145 prostate cancer cells. Conversely, caspase 8 inhibitor Z-IETD-FMK blocked the apoptotic ability of EP to cleave PARP and an increase of sub G1 population in DU 145 prostate cancer cells. Likewise, the silencing of DR 5 suppressed the cleavages of PARP induced by EP in DU 145 prostate cancer cells.ConclusionOverall, our findings suggest that ergosterol peroxide induces apoptosis via activation of death receptor 5 and caspase 8/3 in DU 145 prostate cancer cells as a cancer chemopreventive agent or dietary factor.