benzofurans and Prostatic-Neoplasms

Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell-derived factors such as cytokines and chemokines plays a central role. IL-25, as a member of the IL-17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL-25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL-25 exerts a tumor-suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor-supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type-2 immune responses. Since IL-25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL-25-based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL-25 has a tumor-suppressive function, employing IL-25-enhancing approaches, such as Virulizin

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Bile; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Disease Progression; Female; Humans; Immunity, Cellular; Interleukin-17; Liver Neoplasms; Male; Mice; Neoplasms; Prognosis; Prostatic Neoplasms; Receptors, Interleukin-17; Signal Transduction; Tissue Extracts; Tumor Microenvironment

Herein, apoptotic mechanism of Moracin D was explored in prostate cancer cells in association with peroxisome proliferator-activated receptor gamma (PPAR-γ)-related signaling involved in lipid metabolism. Moracin D augmented cytotoxicity and sub G1 population in PC3 and DU145 prostate cancer cells, while DU145 cells were more susceptible to Moracin D than PC3 cells. Moracin D attenuated the expression of caspase-3, poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2), and B-cell lymphoma-extra-large (Bcl-xL) in DU145 cells. Consistently, Moracin D significantly augmented the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in DU145 cells. Interestingly, Moracin D activated PPAR-γ and phospho-protein kinase C delta (p-PKC-δ) and inhibited phospho-protein kinase C alpha (p-PKC-α) in DU145 cells. Furthermore, STRING bioinformatic analysis reveals that PPAR-γ interacts with nuclear factor-κB (NF-κB) that binds to PKC-α/PKC-δ or protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). Indeed, Moracin D decreased phosphorylation of NF-κB, ERK, and AKT in DU145 cells. Conversely, PPAR-γ inhibitor GW9662 reduced the apoptotic ability of Moracin D to activate caspase 3 and PARP in DU145 cells. Taken together, these findings provide a novel insight that activation of PPAR-γ/p-PKC-δ and inhibition of p-PKC-α are critically involved in Moracin D-induced apoptosis in DU145 prostate cancer cells.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Humans; Male; PPAR gamma; Prostatic Neoplasms; Protein Kinase C-alpha; Protein Kinase C-delta

Prostate cancer (PC) metastasizes to the skeleton forming predominantly sclerotic lesions, and there is currently no cure for bone metastatic disease. The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated as a metastatic driver, but its potential as therapeutic target in bone metastasis has not been investigated. In this study, we evaluated for the first time a STAT3 inhibitor, Napabucasin, as a therapeutic option for bone metastatic PC.. Effects of STAT3 inhibitors, Stattic and Napabucasin, on metastatic potential in PC cells were studied in vitro by assessment of migration capacity, self-renewal potential, and tumorsphere formation. For evaluation of the role of STAT3 in initial skeletal establishment of PC cells as well as in progressed castration-resistant PC (CRPC) in bone, human VCaP prostate cancer cells were inoculated in the tibia of mice which subsequently were treated with the STAT3 inhibitor Napabucasin. Bone specimens were analyzed using computed tomography (CT), immunohistochemistry, and quantitative polymerase chain reaction.. The small molecule STAT3 inhibitors Stattic and Napabucasin both effectively impaired metastatic potential of PC cells in vitro. Furthermore, treatment with Napabucasin prevented metastatic establishment in tibial bones in vivo and thereby also the tumor-induced sclerotic bone response seen in vehicle-treated VCaP xenografts. In addition, treatment with Napabucasin of established bone CRPC significantly decreased both tumor burden and tumor-induced trabecular bone volume compared with effects seen in vehicle-treated animals. Anti-mitotic effects were confirmed by decreased Ki67 staining in Napabucasin-treated xenografts compared with vehicle-treated xenografts. Alterations of gene expression in the femoral bone marrow (BM) niche toward the maintenance of hematopoietic stem cells and the myeloid lineage were demonstrated by quantitative real-time polymerase chain reaction and were further reflected by a substantial increase in the number of erythrocytes in BM of Napabucasin-treated mice. Furthermore, a unique pattern of STAT3 phosphorylation in osteoblasts/stromal cells surrounding the areas of tumor cells was demonstrated immunohistochemically in bone xenograft models using several different PC cell lines.. Inhibition of STAT3 activity disrupts the bone metastatic niche and targets both the skeletal establishment of PC and advanced bone metastatic CRPC in mice, suggesting STAT3 as a candidate for molecular targeted therapies of skeletal metastatic disease.

Topics: Animals; Benzofurans; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyclic S-Oxides; Male; Mice; Naphthoquinones; Prostatic Neoplasms; STAT3 Transcription Factor; Tibia

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.

Topics: Animals; Anticarcinogenic Agents; Benzofurans; Disease Models, Animal; Humans; Male; Mice; Prostatic Neoplasms; Stilbenes

The overexpression of metastasis-associated protein 1 (MTA1) in prostate cancer (PCa) contributes to tumor aggressiveness and metastasis. We have reported the inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of prostatic intraepithelial neoplasia and adenocarcinoma in mouse models by inhibiting MTA1 expression and signaling. In the current study, we investigated the MTA1 targeted anticancer effects of Gnetin C, a resveratrol dimer, in comparison with resveratrol and pterostilbene. Using DU145 and PC3M PCa cells, we found that Gnetin C downregulates MTA1 more potently than resveratrol and pterostilbene. Further, Gnetin C demonstrated significant MTA1-mediated inhibitory effect on cell viability, colony formation, and migration, while showing a more potent induction of cell death than resveratrol or pterostilbene. In addition, we identified Gnetin C-induced substantial ETS2 (erythroblastosis E26 transformation-specific 2) downregulation, which is not only MTA1-dependent, but is also independent of MTA1 as a possible mechanism for the superior anticancer efficacy of Gnetin C in PCa. Together, these findings underscore the importance of novel potent resveratrol dimer, Gnetin C, as a clinically promising agent for the future development of chemopreventive and possibly combinatorial therapeutic approaches in PCa.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Repressor Proteins; Resveratrol; Stilbenes; Trans-Activators

The aim of this study was to investigate the combined effects of usnic acid (UA) and Tamoxifen (Tam) or Enzalutamide (Enz) on hormone receptor-positive breast and prostate cancer (BC and PC), respectively. The antiproliferative and apoptotic effects of Tam or Enz alone and in combination with UA on MCF7 and LNCaP cancer cells were detected. The results of the WST-1 assay indicated that UA was a promising anticancer compound that significantly enhanced the effectiveness of hormone therapy drugs compared with each drug alone (combination index < 1). In addition, the combination of UA with Tam or Enz remarkably induced more cell cycle arrest at the G0/G1 phase and apoptosis than only drug-treated cells (P < 0.01). Consequently, our findings suggest that the combination of UA with Tam or Enz may be a potential therapeutic approach for the treatment of BC and PC and further studies are required to exploit the potential mechanisms of synergistic effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzofurans; Breast Neoplasms; Cell Line, Tumor; Drug Synergism; Female; Humans; Male; Prostatic Neoplasms; Receptors, Cell Surface

Topics: Animals; Benzofurans; Binding Sites; Colchicine; Humans; Male; Mice; Mice, Nude; Neoplasm Proteins; PC-3 Cells; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prostatic Neoplasms; Protein Multimerization; Tubulin; Xenograft Model Antitumor Assays; Zebrafish

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Female; G1 Phase; Humans; Inhibitory Concentration 50; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Resting Phase, Cell Cycle

Four benzofuran-conjugated iridium(III) or rhodium (III)-based metal complexes are synthesized to screen as an inhibitor of STAT3 activity in prostate cancer cells. All complexes show the high stability and solubility in the biological system. In this study, an iridium(III) complex engages STAT3 and NF-κB to inhibit their translocation and transcriptional activities. Moreover, complex 1 shows more potential antiproliferative activity against DU145 cells and suppresses tumor growth in a prostate cancer xenograft mouse without observable adverse effects. Complex 1 may provide the basis for developing new therapeutic strategy in vivo and in vitro for the treatment of advanced prostate cancer.

Topics: Animals; Benzofurans; Cell Line, Tumor; HEK293 Cells; Humans; Iridium; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Prostatic Neoplasms; Random Allocation; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Cadmium, an established carcinogen, is a risk factor for prostate cancer. Induction of autophagy is a prerequisite for cadmium-induced transformation and metastasis. The ability of Psoralidin (Pso), a non-toxic, orally bioavailable compound to inhibit cadmium-induced autophagy to prevent prostate cancer was investigated.. Psoralidin was studied using cadmium-transformed prostate epithelial cells (CTPE), which exhibit high proliferative, invasive and colony forming abilities. Gene and protein expression were evaluated by qPCR, western blot, immunohistochemistry and immunofluorescence. Xenograft models were used to study the chemopreventive effects in vivo.. Cadmium-transformed prostate epithelial cells were treated with Pso resulting in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Psoralidin-treatment of CTPE cells inhibited the expression of Placenta Specific 8, a lysosomal protein essential for autophagosome and autolysosome fusion, which resulted in growth inhibition. Additionally, Pso treatment caused decreased expression of pro-survival signalling proteins, NFκB and Bcl2, and increased expression of apoptotic genes. In vivo, Pso effectively suppressed CTPE xenografts growth, without any observable toxicity. Tumours from Pso-treated animals showed decreased autophagic morphology, mesenchymal markers expression and increased epithelial protein expression.. These results confirm that inhibition of autophagy by Pso plays an important role in the chemoprevention of cadmium-induced prostate carcinogenesis.

Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Benzofurans; Blotting, Western; Cadmium; Carcinogenesis; Cell Proliferation; Cells, Cultured; Coumarins; Fluorescent Antibody Technique; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Lysosomes; Male; Mice, Nude; Neoplasm Transplantation; NF-kappa B; Polymerase Chain Reaction; Prostate; Prostatic Neoplasms; Proteins; Proto-Oncogene Proteins c-bcl-2

Lichens are an interesting source of potential anti-tumor compounds, among which usnic acid and atranorin seem to be the most promising, but their impact on invasive potential of tumor cells has not yet been comprehensively addressed. The aim of the study was focused on the impact of the two lichen metabolites, on the viability (by Trypan blue test and fluoresceine diacetate and ethidium bromide assay), proliferation (cell counting in a Bürker's chamber), apoptosis (flow cytometry analysis and Western blot) and motile activity (cell movement recording and image analysis) and actin cytoskeleton organization (immunofluorescent staining) of melanoma HTB-140, prostate cancers DU-145 and PC-3, normal human skin fibroblasts and prostate epithelial PNT2 cells, with special emphasis to their selectivity and versatility.. Both compounds exerted strong inhibitory effects on cancer cell proliferation, migration and actin cytoskeleton organization, while their effect on apoptosis process was less relevant. The impact of usnic acid on the examined cancer cells was found more efficient in comparison to atranorin. Also, selective effect of both agents on tumor cells was observed.. The ability of usnic acid and atranorin to inhibit cancer cells motility may have future implications for development of new therapeutic strategies targeted at the interference with the metastatic cascade.

Topics: Actins; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cytostatic Agents; Fibroblasts; Humans; Hydroxybenzoates; Male; Melanoma; Prostatic Neoplasms

The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype.

Topics: Adrenergic alpha-1 Receptor Antagonists; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cytostatic Agents; Dioxanes; Humans; Male; Prostatic Neoplasms; Receptors, Adrenergic, alpha-1; RNA, Messenger

Most studies on the relationship between Agent Orange and prostate cancer have focused on US veterans of the Vietnam War. There have been few studies focusing on the relationship between levels of prostate-specific antigen (PSA) and dioxins or steroid hormones in Vietnamese men. In 2009-2011, we collected blood samples from 97 men who had resided in a "dioxin hotspot" and 85 men from a non-sprayed region in Vietnam. Then levels of PSA, dioxins, and steroid hormones were analyzed. Levels of most dioxins, furans, and non-ortho polychlorinated biphenyls were higher in the hotspot than those in the non-sprayed region. Levels of testosterone, dehydroepiandrosterone, and estradiol differed significantly between the hotspot and the non-sprayed region, but there were no correlations between levels of PSA and steroid hormones and dioxins in either of the two regions. Our findings suggest that PSA levels in Vietnamese men are not associated with levels of dioxin or steroid hormones in these two regions.

Topics: 2,4-Dichlorophenoxyacetic Acid; 2,4,5-Trichlorophenoxyacetic Acid; Aged; Agent Orange; Benzofurans; Dioxins; Environmental Pollutants; Furans; Gonadal Steroid Hormones; Humans; Male; Middle Aged; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Prostate-Specific Antigen; Prostatic Neoplasms; Steroids; Testosterone; Vietnam

Prostate cancer is one of the most common malignant tumors in males and it has become a major worldwide public health problem. This study characterizes the encapsulation of Nor-β-lapachone (NβL) in poly(d,l-lactide-co-glycolide) (PLGA) microcapsules and evaluates the cytotoxicity of the resulting drug-loaded system against metastatic prostate cancer cells. The microcapsules presented appropriate morphological features and the presence of drug molecules in the microcapsules was confirmed by different methods. Spherical microcapsules with a size range of 1.03 ± 0.46 μm were produced with an encapsulation efficiency of approximately 19%. Classical molecular dynamics calculations provided an estimate of the typical adsorption energies of NβL on PLGA. Finally, the cytotoxic activity of NβL against PC3M human prostate cancer cells was demonstrated to be significantly enhanced when delivered by PLGA microcapsules in comparison with the free drug.

Topics: Antineoplastic Agents; Benzofurans; Capsules; Cell Line, Tumor; Cell Survival; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Humans; Inhibitory Concentration 50; Lactic Acid; Male; Models, Molecular; Molecular Conformation; Molecular Structure; Naphthoquinones; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms; Spectrum Analysis, Raman

Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis.

Topics: Acetylcysteine; Antioxidants; Apoptosis; Benzofurans; beta Catenin; Cadherins; Caspase 3; Caspase 9; Catalase; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coumarins; Cytochromes c; Enzyme Activation; Epithelial-Mesenchymal Transition; Humans; Male; Membrane Potential, Mitochondrial; Neoplasm Invasiveness; Oxidative Stress; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Reactive Oxygen Species; Snail Family Transcription Factors; Superoxide Dismutase; Superoxide Dismutase-1; Transcription Factors; Transcription, Genetic

Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydro-benzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild‑type (p53-wt) LNCaP (androgen‑dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Cell Proliferation; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; MAP Kinase Signaling System; Naphthyridines; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt

To observe the clinical effect of tashinone IIA combined with endocrine therapy in treating advanced-stage prostate cancer. 96 cases of advanced-stage prostate cancer were divided into observation group (44 cases received treatment) and control group (46 cases received treatment). Control group was given leuprolide acetate 3.75 mg hypodermic injection per month, combined with bicalutamide 50 mg per os per day for a 6-month treatment course. Observation group was given tashinone IIA injection 60 mg intravenously per day. They were treated for 2 weeks and paused for 2 weeks as one treatment course for six courses in total. After treating for 6 months, the general therapeutic effect, prostate-specific antigen (PSA), free prostate-specific antigen (f-PSA), hemoglobin (Hb), the quality of life questionnaire Core 30 (QLQ-C30), traditional Chinese medicine symptom information score, international prostate symptom score (I-PSS), and adverse effect rate were observed. The effective rate of observation group and control group was 52.3 and 28.3 %, respectively (P < 0.05). PSA, f-PSA, and Hb in two groups had no statistical difference before treatment. PSA and f-PSA in both groups obviously decreased compared to those before treatment, and they were lower in observation group than in control group (P < 0.01). Hb in observation group was higher than before treatment, whereas Hb in control group was lower than before treatment (P < 0.01). Life quality, motive score, the traditional Chinese medicine symptom score, and I-PSS in observation group were significantly better those that in control group after treatment (P < 0.01). Laboratory tests such as hemogram, and liver and kidney function had no obvious change, and adverse effect rate had no statistical difference. Routine endocrine treatment combined with tashinone IIA can enhance the clinical effects on treating advanced-stage prostate cancer and improve the clinical symptom score.

Topics: Aged; Anilides; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Hemoglobins; Humans; Leuprolide; Male; Neoplasm Staging; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Tosyl Compounds; Treatment Outcome

A naturally occurring benzofuran derivative, Ebenfuran III (Eb III), was investigated for its antiproliferative effects using the DU-145 prostate cell line. Eb III was isolated from Onobrychis ebenoides of the Leguminosae family, a plant endemic in Central and Southern Greece. We have previously reported that Eb III exerts significant cytotoxic effects on certain cancer cell lines. This effect is thought to occur via the isoprenyl moiety at the C-5 position of the molecule. The study aim was to gain a deeper understanding of the pharmacological effect of Eb III on DU-145 cell death at the translational level using a relative quantitative and temporal proteomics approach. Proteins extracted from the cell pellets were subjected to solution phase trypsin proteolysis followed by iTRAQ-labeling. The labeled tryptic peptide extracts were then fractionated using strong cation exchange chromatography and the fractions were analyzed by nanoflow reverse phase ultraperformance liquid chromatography-nanoelectrospray ionization-tandem mass spectrometry analysis using a hybrid QqTOF platform. Using this approach, we compared the expression levels of 1360 proteins analyzed at ≤ 1% global protein false discovery rate (FDR), commonly present in untreated (control, vehicle only) and Eb III-treated cells at the different exposure time points. Through the iterative use of Ingenuity Pathway Analysis with hierarchical clustering of protein expression patterns, followed by bibliographic research, the temporal regulation of the Calpain-1, ERK2, PAR-4, RAB-7, and Bap31 proteins were identified as potential nodes of multipathway convergence to Eb III induced DU-145 cell death. These proteins were further verified with Western blot analysis. This gel-free, quantitative 2DLC-MS/MS proteomics method effectively captured novel modulated proteins in the DU-145 cell line as a response to Eb III treatment. This approach also provided greater insight to the multifocal and combinatorial signaling pathways implicated in Eb III-induced cell death.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis Regulatory Proteins; Benzofurans; Calpain; Cell Death; Cell Line, Tumor; Chromatography, Reverse-Phase; Cluster Analysis; Humans; Male; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Prostatic Neoplasms; Proteins; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins; Resorcinols; Tandem Mass Spectrometry

Etk is a non-receptor tyrosine kinase, which provides a strong survival signal in human prostate cancer cells. Src, another tyrosine kinase that cross-activates with Etk, has been shown to play an important role in prostate cancer metastasis. Herein, we discovered a new class of Etk inhibitors. Within those inhibitors, CTA095 was identified as a potent Etk and Src dual inhibitor. CTA095 was found to induce autophagy as well as apoptosis in human prostate cancer cells. In addition, CTA095 inhibited HUVEC cell tube formation and "wound healing" of human prostate cancer cells, implying its role in inhibition of angiogenesis and metastasis of human prostate cancer. More interestingly, CTA095 could overcome Src inhibitor resistance in prostate cancer cells. It induces apoptosis in Src inhibitor resistant prostate cancer cells, likely through a mechanism of down regulation of Myc and BCL2. This finding indicates that simultaneously targeting Etk and Src could be a promising approach to overcome drug resistance in prostate cancer.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Benzofurans; Binding Sites; Cell Movement; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Enzyme Activation; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Models, Molecular; Phosphorylation; Prostatic Neoplasms; Protein Binding; Protein Conformation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Quinoxalines; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Abnormally high activity of protein kinase CK2 is linked to various diseases including cancer. Therefore, the inhibition of CK2 is a promising therapeutic strategy to fight this disease.. We screened a library of synthetic molecules concerning their capacity to inhibit CK2. The activity of CK2 and their IC50 and Ki values were determined by a capillary electrophoresis assay. The effects of the inhibitor in a cell culture model were analyzed by cell counting, a viability assay, cytofluorimetry and Western blot.. The best CK2 inhibitor found in this screen was 6,7-dichloro-1,4-dihydro-8-hydroxy-4-[(4-methylphenylamino)methylen]dibenzo [b,d]furan-3(2H)-one, which we refer to as "TF". TF showed tight binding to CK2 with low IC50 (29 nM) and Ki (15 nM) values. TF inhibited only seven out of 61 human kinases tested (>70% inhibition). Incubation of LNCaP cells with 50 μM TF for 48 h decreased the intracellular CK2 activity by 50%, confirming that the inhibitor is membrane permeable. The decrease in activity was correlated with a severe reduction in cell viability. The reduction in cell viability is at least partly due to the induction of apoptosis.. In many cancers the protein kinase CK2 is significantly up-regulated and supports the neoplastic phenotype. New therapeutic strategies should be based on diverse reliable inhibitors to reverse the abnormal high levels to normal settings.

Topics: Apoptosis; Benzofurans; Blotting, Western; Casein Kinase II; Cell Line, Tumor; Cell Survival; Humans; Inhibitory Concentration 50; Kinetics; Male; Phosphorylation; Prostatic Neoplasms; Protein Kinase Inhibitors; Up-Regulation

Numerous compounds detected in medical plants and dietary components or supplements possess chemopreventive, antitumor and immunomodulatory properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anticancer factor that induces apoptosis selectively in cancer cells. However, some tumor cells are resistant to TRAIL-mediated apoptosis. Naturally occurring agents could sensitize TRAIL-resistant cancer cells and augment their apoptotic activity.We examined the cytotoxic and apoptotic effects of neobavaisoflavone and psoralidin in combination with TRAIL on LNCaP prostate cancer cells. The cytotoxicity was evaluated by MTT and LDH assays. The apoptosis was detected using Annexin V-FITC by flow cytometry and fluorescence microscopy. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrated that neobavaisoflavone and psoralidin sensitized TRAIL-resistant cells and markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Cotreatment of LNCaP cells with 100 ng/ml TRAIL and 50 μM neobavaisoflavone or 50 μM psoralidin increased the percentage of the apoptotic cells to 77.5±0.5% or 64.4±0.5%, respectively. The data indicate the potential role of the bioactive compounds isolated from the medicinal plant Psoralea corylifolia (neobavaisoflavone and psoralidin) in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Coumarins; Flow Cytometry; Humans; Isoflavones; Male; Microscopy, Fluorescence; Prostatic Neoplasms; Psoralea; TNF-Related Apoptosis-Inducing Ligand

The tumor necrosis factor (TNF) receptor super family comprises of members that induce two distinct signaling cascades, leading to either cell survival or apoptosis. However, in prostate cancer (PCa), TNF-mediated prosurvival signaling is the predominant pathway that leads to cell survival and resistance to therapy. Although inhibition of TNF signaling by pharmacological agents or monoclonal antibodies has gained importance in the field of cancer therapy, toxicity to normal cells has impaired their extensive use for cancer treatment. We previously identified a natural, nontoxic compound psoralidin that inhibited viability and induced apoptosis in androgen independent prostate cancer (AIPC) cells. Thus, the goal of our study is to investigate whether psoralidin inhibits TNF-mediated prosurvival signaling in AIPC cells. Our results suggest that psoralidin inhibits constitutive and TNF-induced expression of TNF-alpha and its downstream prosurvival signaling molecules such as NF-kappaB and Bcl-2 in AIPC cells. On the other hand, psoralidin simultaneously induces the death receptor (DR)-mediated apoptotic signaling eventually causing the activation of caspase cascade and resultant induction of apoptosis. Oral administration of psoralidin inhibits expression of TNF-alpha and NF-kappaB/p65 in tumor sections, resulting in tumor regression in PC-3 xenografts. Our results suggest that psoralidin inhibits TNF-mediated survival signaling in AIPC and thus is a potent therapeutic agent for prostate cancer.

Topics: Androgens; Animals; Apoptosis; Benzofurans; Caspases; Cell Line, Tumor; Cell Survival; Coumarins; Down-Regulation; Drug Resistance, Neoplasm; Humans; Male; Mice; NF-kappa B; Prostatic Neoplasms; Receptors, Death Domain; Recombinant Proteins; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling, such as the Raf, mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 cascades. EGFR activation has been implicated in the transition of prostate cancer from androgen dependence to independence. Therefore, inhibition of EGFR may effectively suppress prostate cancer growth and progression. The goal of this study was to determine whether the natural compound psoralidin alters EGFR-mediated signaling resulting in the inhibition of prostate cancer growth. Results suggest that inhibition of EGFR alone (by serum deprivation) fails to induce stress-mediated protein kinases (SAPK), namely, Jun NH(2)-terminal kinase/c-Jun signaling, in androgen-independent prostate cancer (AIPC) cells. Treatment with psoralidin, however, inhibited both constitutive and EGF-induced EGFR activation and simultaneously triggered SAPK signaling, resulting in the induction of apoptosis in AIPC cells. In addition, psoralidin downregulated EGFR-regulated MAPK signaling and inhibited cell proliferation in AIPC cells. Oral administration of psoralidin effectively suppressed PC-3 xenograft tumors in nude mice. Compared with control tumors, inhibition of pEGFR expression and an increase in the phosphorylation, activation, and nuclear translocation of c-Jun were observed in psoralidin-treated tumor sections. Our studies suggest that psoralidin may be a potent therapeutic agent that modulates EGFR-mediated key epigenetic events in AIPC.

Topics: Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Coumarins; Down-Regulation; Enzyme Activation; ErbB Receptors; Humans; Immunohistochemistry; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Mice; Phosphorylation; Prostatic Neoplasms; Transfection; Transplantation, Heterologous

The aryl hydrocarbon receptor (AhR) is a basic-helix-loop-helix transcription factor that binds halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and endogenous compounds. We previously reported that AhR null (Ahr(-/-)) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice on a C57BL/6J background develop prostate tumors with much greater frequency than AhR wild-type (Ahr(+/+)) TRAMP mice, suggesting that the AhR has tumor suppressor properties. Because AhR signaling pathway inactivation increased susceptibility to prostate tumorigenesis, we tested the hypothesis that a selective AhR modulator (SAhRM), 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), can protect against prostate tumorigenesis. TRAMP mice on the standard C57BL/6JxFVB genetic background were fed 0, 10, or 40mg 6-MCDF/kg diet beginning at 8 weeks of age. Tumor incidence, pelvic lymph node metastasis, and serum vascular endothelial growth factor (VEGF) concentrations were determined at 140 days of age. Prostate tumor incidence and size were not significantly reduced in mice fed 6-MCDF. However, the frequency of pelvic lymph node metastasis was reduced fivefold in mice fed the 40mg 6-MCDF/kg diet. Serum VEGF concentrations were also reduced by 6-MCDF treatment, particularly in mice without prostate tumors, and 6-MCDF was shown to act directly on cultured prostates to inhibit VEGF secretion. Together, these results suggest that 6-MCDF inhibits metastasis, in part, by inhibiting prostatic VEGF production prior to tumor formation. This is the first report that 6-MCDF can confer protection against prostate cancer in vivo.

Topics: Animals; Benzofurans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organ Culture Techniques; Pelvic Neoplasms; Prostatic Neoplasms; Receptors, Aryl Hydrocarbon

The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-kappaB and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.

Topics: Animals; Benzofurans; Cell Line, Tumor; Cell Proliferation; Coumarins; Drug Screening Assays, Antitumor; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases; Plant Preparations; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction

LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and an Ah-responsive reporter gene. Similar results were obtained with the selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however, TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR) crosstalk was investigated in cells transfected with constructs containing the androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the -244 to -96 region of this promoter (pARR(3)). Ten nanomolar dihydrotestosterone (DHT) and 17 beta-estradiol (E2) induced transactivation in LNCaP cells transfected with pPB or pARR(3); however, inhibitory AhR-AR crosstalk was observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or E2-induced transactivation in ZR-75 human breast cancer cells, indicating that these interactions were promoter and cell context-dependent. Both E2 and DHT stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF decreased AR protein levels. These results indicate that inhibitory AhR-AR crosstalk in prostate cancer cells is complex and for some responses, AR protein stability may play a role.

Topics: Benzofurans; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cytochrome P-450 CYP1A1; Dihydrotestosterone; Estradiol; Female; Genes, Reporter; Humans; Male; Polychlorinated Dibenzodioxins; Promoter Regions, Genetic; Prostatic Neoplasms; Receptors, Androgen; Receptors, Aryl Hydrocarbon; Time Factors; Transcriptional Activation

A unique benzofuran named suillusin was isolated from the methanolic extract of the fruiting body of the mushroom Suillus granulatus. Its structure was assigned on the basis of various spectroscopic analyses as a highly substituted novel 1H-cyclopenta[b]benzofuran (1). Suillusin is suggested to be biogenerated from polyporic acid.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Basidiomycota; Benzofurans; Cell Survival; Chromatography, High Pressure Liquid; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; Korea; Lung Neoplasms; Magnetic Resonance Spectroscopy; Male; Melanoma; Molecular Structure; Ovarian Neoplasms; Prostatic Neoplasms; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Tumor Cells, Cultured; Vitamin E