Article

Suppression of growth and invasive behavior of human prostate cancer cells by ProstaCaid (TM): Mechanism of activity

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  • Purdue Research Park, Indianapolis, United States
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Abstract

Since the use of dietary supplements as alternative treatments or adjuvant therapies in cancer treatment is growing, a scientific verification of their biological activity and the detailed mechanisms of their action are necessary for the acceptance of dietary supplements in conventional cancer treatments. In the present study we have evaluated the anti-cancer effects of dietary supplement ProstaCaid™ (PC) which contains mycelium from medicinal mushrooms (Ganoderma lucidum, Coriolus versicolor, Phellinus linteus), saw palmetto berry, pomegranate, pumpkin seed, green tea [40% epigallocatechin-3-gallate (EGCG)], Japanese knotweed (50% resveratrol), extracts of turmeric root (BCM-95®), grape skin, pygeum bark, sarsaparilla root, Scutellaria barbata, eleuthero root, Job's tears, astragalus root, skullcap, dandelion, coptis root, broccoli, and stinging nettle, with purified vitamin C, vitamin D3, selenium, quercetin, citrus bioflavonoid complex, β sitosterolzinc, lycopene, α lipoic acid, boron, berberine and 3.3'-diinodolymethane (DIM). We show that PC treatment resulted in the inhibition of cell proliferation of the highly invasive human hormone refractory (independent) PC-3 prostate cancer cells in a dose- and time-dependent manner with IC50 56.0, 45.6 and 39.0 µg/ml for 24, 48 and 72 h, respectively. DNA-microarray analysis demonstrated that PC inhibits proliferation through the modulation of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes. In addition, PC also suppresses metastatic behavior of PC-3 by the inhibition of cell adhesion, cell migration and cell invasion, which was associated with the down-regulation of expression of CAV1, IGF2, NR2F1, and PLAU genes and suppressed secretion of the urokinase plasminogen activator (uPA) from PC-3 cells. In conclusion, the dietary supplement PC is a promising natural complex with the potency to inhibit invasive human prostate cancer.

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... C. Rhizoma is one of the ingredients (Yan and Katz, 2010). Prostacaid suppresses cell proliferation by inducing G 2 /M phase arrest, induction of apoptosis and regulating the expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6, and PCNA genes (Yan and Katz, 2010;Jiang et al., 2011). Furthermore, it also inhibits the metastatic behavior of the human prostate cancer cells by inhibiting cell adhesion, invasion, and invasion, by downregulating of the expression of the CAV1, NR2F1, PLAU, and IGF2 genes and suppressing the secretion of urokinase plasminogen activator (Jiang et al., 2011). ...
... Prostacaid suppresses cell proliferation by inducing G 2 /M phase arrest, induction of apoptosis and regulating the expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6, and PCNA genes (Yan and Katz, 2010;Jiang et al., 2011). Furthermore, it also inhibits the metastatic behavior of the human prostate cancer cells by inhibiting cell adhesion, invasion, and invasion, by downregulating of the expression of the CAV1, NR2F1, PLAU, and IGF2 genes and suppressing the secretion of urokinase plasminogen activator (Jiang et al., 2011). ...
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Cancer is a serious disease with an increasing number of reported cases and high mortality worldwide. Gastrointestinal cancer defines a group of cancers in the digestive system, e.g., liver cancer, colorectal cancer, and gastric cancer. Coptidis Rhizoma ( C. Rhizoma ; Huanglian, in Chinese) is a classical Chinese medicinal botanical drug for the treatment of gastrointestinal disorders and has been shown to have a wide variety of pharmacological activity, including antifungal, antivirus, anticancer, antidiabetic, hypoglycemic, and cardioprotective effects. Recent studies on C. Rhizoma present significant progress on its anticancer effects and the corresponding mechanisms as well as its clinical applications. Herein, keywords related to C. Rhizoma , cancer, gastrointestinal cancer, and omics were searched in PubMed and the Web of Science databases, and more than three hundred recent publications were reviewed and discussed. C. Rhizoma extract along with its main components, berberine, palmatine, coptisine, magnoflorine, jatrorrhizine, epiberberine, oxyepiberberine, oxyberberine, dihydroberberine, columbamine, limonin, and derivatives, are reviewed. We describe novel and classic anticancer mechanisms from various perspectives of pharmacology, pharmaceutical chemistry, and pharmaceutics. Researchers have transformed the chemical structures and drug delivery systems of these components to obtain better efficacy and bioavailability of C. Rhizoma . Furthermore, C. Rhizoma in combination with other drugs and their clinical application are also summarized. Taken together, C. Rhizoma has broad prospects as a potential adjuvant candidate against cancers, making it reasonable to conduct additional preclinical studies and clinical trials in gastrointestinal cancer in the future.
... CV contains different kinds of compounds, from which the effects of polysaccharopeptides (PSP) and polysaccharide K (PSK) have been extensively studied. PSP has anti-cancer effect against various cancer cell lines (Jiang et al., 2011) and they can also act as an immune-enhancer of the immune system under different mechanisms (Cui and Chisti, 2003;Huang et al., 2013). PSK is a proprietary product developed for cancer treatment in Japan. ...
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Ethnopharmacological relevance Coriolus versicolor (CV) has been used in traditional Chinese medicine for over 2000 years as a premium medicine for enhancing good health and longevity. The immunomodulatory and anti-cancer effects of polysaccharopeptides (PSP) from cultured CV have been extensively studied; however, the effect and the mechanism of action of other small molecules from CV remain unknown. Aim of the study: we aim to examine the immunomodulatory and anti-cancer effects of the small molecules from CV (SMCV) and identify the active compounds that are responsible for the biological effects against glioblastoma multiforme cells. Materials and methods The effects of SMCV/active compound on cytokine and MMP mRNA expressions and productions were assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Active compound from SMCV was identified with a bioassay-guided fractionation scheme. The potential mode of action of the active compound was further investigated by identifying the cell signaling pathway. The protein expressions of phospho-ERK, phospho-JNK and phospho-p38 MAPKs were measured by Western Blotting. The anti-invasive effect of SMCV/bioactive compound against T98G, lung carcinoma (A549), and breast adenocarcinoma (MDA-MB-231) cells were determined using Matrigel Invasion Chamber. Results Our results showed that SMCV had strong immunomodulatory effect by suppressing LPS-induced TNF-α production, whereas increasing poly I:C-induced IFN-β level in PBMac. SMCV not only possessed indirect anti-cancer effect by suppressing TNF-α-induced MMP-3 production in glioblastoma T98G cells, but also directly reduced the invasion ability of malignant cells including T98G, A549 and MDA-MB-231. Using bioassay-guided fractionation scheme, we isolated 9-KODE methyl ester (compound AM) that was responsible for the bioactivity of SMCV. This compound suppressed TNF-α-induced MMP-3 production in T98G cells and the suppression may be correlated with the inactivation of p38 mitogen-activated protein kinase (MAPK) pathway. Moreover, compound AM also directly reduced T98G cell invasion. Conclusion Results of our present study provides scientific evidence that SMCV possesses immunomodulatory and anti-cancer effects. Its bioactive compound, compound AM, is a potential new drug candidate against the invasion and metastasis of glioblastoma cells.
... styriaca showed significant inhibitive properties against hyperplastic and cancer cells, [331]. The protective role of pumpkin against prostate cancer has been also reported in in vitro and in vivo studies where pumpkin seeds were one of the ingredients of polyherbal formulations [332,333]. Moreover, according to Friedrich et al. [334] and Hong et al. [335] administration of pumpkin seed oil in patients with benign prostatic hyperplasia (BPH) may significantly improve symptoms based on the international prostate symptom score (IPPS), without however reducing prostate volume and prostate specific antigen. ...
... Natural compounds, such as curcumin [7][8][9] and moringa [10], or polybotanical compounds, such as BreastDefend and ProstaCaid [11,12] were found to potentiate the effect of standard chemotherapy. One of such natural products is the extract of Aesculus hippocastanum (the horse chestnut) seeds that has been used in China as an analgesic and an antipyretic agent [13]. ...
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Background. There is an urgent need to develop new treatment strategies and drugs for pancreatic cancer that is highly resistant to radio-chemotherapy. Aesculus hippocastanum (the horse chestnut) known in Chinese medicine as a plant with anti-inflammatory, antiedema, antianalgesic, and antipyretic activities. The main active compound of this plant is Escin (C54H84O23). Objective. To evaluate the effect of Escin alone and combined with chemotherapy on pancreatic cancer cell survival and to unravel mechanism(s) of Escin anticancer activity. Methods. Cell survival was measured by XTT colorimetric assay. Synergistic effect of combined therapy was determined by CalcuSyn software. Cell cycle and induction of apoptosis were evaluated by FACS analysis. Expression of NF- κ B-related proteins (p65, I κ Bα, and p-I κ Bα) and cyclin D was evaluated by western blot analysis. Results. Escin decreased the survival of pancreatic cancer cells with IC50 = 10-20 M. Escin combined with gemcitabine showed only additive effect, while its combination with cisplatin resulted in a significant synergistic cytotoxic effect in Panc-1 cells. High concentrations of Escin induced apoptosis and decreased NF- κ B-related proteins and cyclin D expression. Conclusions. Escin decreased pancreatic cancer cell survival, induced apoptosis, and downregulated NF- κ B signaling pathway. Moreover, Escin sensitized pancreatic cancer cells to chemotherapy. Further translational research is required.
... In addition, pumpkin seeds are often tested in a complex mixture with other plants and ingredients. For example, Jiang et al. [11,12] demonstrated inhibition of prostate cancer in vitro and in a xenograft model with a polyherbal dietary supplement where pumpkin seeds are only one of 33 ingredients. This makes an interpretation of the efficacy of individual extracts and compounds impossible. ...
Article
Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. Pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~ 40–50% was observed for all cell lines, with the exception of HDF-5, which showed with ~ 20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate.
... In addition, another advantage of resveratrol is its relative safety and low incidence of side effects. No apparent side effects have been reported since resveratrol became a commercial supplement [45]. Resveratrol exhibits such a low toxicity that it does not cause side effects even in the bone marrow or the digestive tract, which are highly regenerative tissues. ...
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Background: Intra-abdominal adhesions are a very common complication following abdominal surgery. Our previous studies have demonstrated that the inhibition of inflammation at the sites of peritoneal injury can prevent the formation of intra-abdominal adhesions. Resveratrol is a natural extract with a broad range of anti-inflammatory effects. Therefore, we propose that resveratrol can reduce the formation of intra-abdominal adhesions after surgery. The aim of this study was to investigate the effect of resveratrol on intra-abdominal adhesion prevention in a rat model with surgery-induced peritoneal adhesions. Materials and methods: The cecum wall and its opposite parietal peritoneum were abraded following laparotomy to induce intra-abdominal adhesion formation. Varying doses of resveratrol were administered to the animals. On the eighth day after surgery, the adhesion score was assessed using a visual scoring system. Picrosirius red staining and a hydroxyproline assay were used to assess the amount of collagen deposition in the adhesion tissues. The levels of serum interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and transforming growth factor beta-1 (TGF-β1) were determined by an enzyme-linked immunosorbent assay (ELISA). Western blotting was performed to determine the protein expression of TGF-β1, fibrinogen, and α-smooth muscle actin (α-SMA) in rat peritoneal adhesion tissue. Real-time RT-PCR was performed to quantify the mRNA expression of TGF-β1, fibrinogen, and α-SMA. Results: Resveratrol significantly reduced intra-abdominal adhesion formation and fibrin deposition in the rat model. Furthermore, resveratrol significantly reduced the serum levels of IL-6, TNF-α, and TGF-β1. The protein and mRNA expression of TGF-β1, fibrinogen, and α-SMA in the rat peritoneum and adhesion tissues were also down-regulated due to resveratrol intervention. Conclusion: Resveratrol can effectively prevent the formation of postoperative intra-abdominal adhesions in a rat model. This effect may be related to the suppression of inflammatory cytokine expression in the injured peritoneum by resveratrol. This study suggests that resveratrol may be a new and effective anti-adhesive agent that is worthy of further study and has potential application value.
... For instance, Pakdel and co-workers proved that reinforced expression of NR2F1 in breast cancer cells might contribute to losing the epithelial phenotype and acquiring the mesenchymal characteristics [11]. Similarly, Jiang et al. identified that the dietary supplement ProstaCaid™ (PC) could repress cell migration and invasiveness in prostate cancer by reducing NR2F1 levels, thus, inhibiting metastatic behavior [52]. Furthermore, hypoxia-induced NR2F1-AS1 expression directly augmented NR2F1 levels to favor pancreatic cancer cell migration and invasion through up-regulating AKT/mTOR signaling [50]. ...
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The mechanism underlying platinum resistance in ovarian cancer (OC) remains unclear. We used bioinformatic analyses to screen differentially expressed genes responsible for platinum resistance and explore NR2F1′s correlation with prognostic implication and OC staging. Moreover, Gene-set enrichment analysis (GSEA) and Gene Ontology (GO) analyses were used for pathway analysis. Epithelial-mesenchymal transition (EMT) properties, invasion, and migration capacities were analyzed by biochemical methods. The association between NR2F1 and cancer-associated fibroblast (CAF) infiltration and immunotherapeutic responses were also researched. A total of 13 co-upregulated genes and one co-downregulated gene were obtained. Among them, NR2F1 revealed the highest correlation with a poor prognosis and positively correlated with OC staging. GSEA and GO analysis suggested the induction of EMT via TGFβ-1 might be a possible mechanism that NR2F1 participates in resistance. In vitro experiments showed that NR2F1 knockdown did not affect cell proliferation, but suppressed cell invasion and migration with or without cisplatin treatment through the EMT pathway. We also found that NR2F1 could regulate TGF-β1 signaling, and treating with TGF-β1 could reverse these effects. Additionally, NR2F1 was predominantly associated with immunosuppressive CAF infiltration, which might cause a poor response to immune check blockades. In conclusion, NR2F1 regulates TGF-β1-mediated EMT affecting platinum sensitivity and immune response in OC patients.
... Berberine and hormone are important representatives of the alkaloid group. The mechanism of action of highly aromatic planar quaternary alkaloids such as berberine and harmane is attributed to their ability to intercalate with DNA (Jiang et al. 2011). ...
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Background: To test the antimicrobial activity of different extracts and fermentation broth from puffball(Bovistella radicata), the different extracts and fermentation broth of puffball were prepared, the active fraction was investigated by UPLC-UV-MS and semi-preparative chromatograph. Results: Through zones of inhibition (ZOI) and minimum inhibitory concentrations (MIC) tests, the supernatant of fermentation possessed best antimicrobial activity in all extracts whose MIC value is 31.2 μg/ml against T. rubrum, T. mentagrophytes, S. aureus and P. aeruginosa. And ZOI value is 29.01, 21.02, 35.02, 28.01 mm against T. rubrum, T. mentagrophytes, S. aureus and P. aeruginosa. Then we compare the puffball fermentation supernatant with blank contrast by LC-MS. There are the characteristic peaks named PBR-1 and PBR-2 with the puffball fermentation supernatant, the separation of compound PBR-1 and PBR-2 was done on semi-preparative C18 column and the MIC and ZOI of compound PBR-1 and PBR-2 are 15.6 μg/ml and 34 mm with the antifungal test. Conclusions: The fermentation supernatant and compound PBR-1 and PBR-2 have promising antifungal activity against T. rubrum and T. mentagrophytes.
... We observed that lycopene not only decreased UVB-induced G1-S transition, but also reduced the expression of CDK2 and CDK4. This is in consistent with previous reports that lycopene blocked CDK2 and CDK4 kinase activity which are also closely associated with the occurrence of skin cancer [Nahum et al., 2001;Jiang et al., 2011]. Furthermore, Nahum et al. [2006] also suggests that attenuation of cyclin D1 levels by lycopene and consequent inhibition of cell cycle progression in G0/ G1 phase are the important mechanisms for the reduction of the mitogenic action. ...
Article
Lycopene, one of the most potent anti-oxidants, has been reported to exhibit potent anti-proliferative properties in a wide range of cancer cells through modulation of the cell cycle and apoptosis. Forkhead box O3a (FOXO3a) plays a pivotal role in modulating the expression of genes involved in cell death. Herein, we investigated the role of FOXO3a signaling in the anti-cancer effects of lycopene. Results showed that lycopene pretreatment attenuated UVB-induced cell hyper-proliferation and promoted apoptosis, accompanied by decreased cyclin-dependent kinase 2 (CDK2) and CDK4 complex in both human keratinocytes and SKH-1 hairless mice. FOXO3a is phosphorylated in response to UVB irradiation and sequestered in the cytoplasm, while lycopene pretreatment rescued this sensitization. Gene ablation of FOXO3a attenuated lycopene-induced decrease in cell hyper-proliferation, CDK2 and CDK4 complex, indicating a critical role of FOXO3a in the lycopene-induced anti-proliferative effect of keratinocytes during UVB irradiation. Transfection with FOXO3a siRNA inhibited the lycopene-induced increase in cell apoptosis, BAX and cleaved PARP expression. Moreover, loss of AKT induced further accelerated lycopene-induced FOXO3a dephosphorylation, while loss of mechanistic target of rapamycin complex 2 (mTORC2) by transfection with RICTOR siRNA induced levels of AKT phosphorylation comparable to those obtained with lycopene. In contrast, overexpression of AKT or mTORC2 decreased the effects of lycopene on the expression of FOXO3a as well as AKT phosphorylation, suggesting that lycopene depends on the negative modulation of mTORC2/AKT signaling. Taken together, our findings demonstrate that the mTORC2/AKT/FOXO3a axis plays a critical role in the anti-proliferative and pro-apoptotic effects of lycopene in UVB-induced photocarcinogenesis. This article is protected by copyright. All rights reserved.
... The focus of most these reports has been on paclitaxel [20][21][22][23]27,28,31], however, there has also been information on other commonly used cytostatics, like cisplatin [27] and cyclophosphamide [42][43][44]. Therefore, there is currently a lot of understanding that anticancer drugs should kill tumor cells as well as prevent metastasis at the same time and a high demand exists for novel mono-and/or combination therapies with an ability to exert such an effect [45][46][47]. ...
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The identification and development of new agents with a therapeutic potential as well as novel drug combinations are gaining the attention of scientists and clinicians as a plausible approach to improve therapeutic regimens for chemoresistant tumors. We have recently reported that the flavonoid fisetin (FIS), at physiologically attainable concentrations, acts synergistically with clinically achievable doses of paclitaxel (PTX) to produce growth inhibitory and pro-death effects on A549 human non-small cell lung cancer (NSCLC) cells. To further investigate a potential therapeutic efficacy of the combination of fisetin with paclitaxel, we decided to assess its impact on metastatic capability of A549 cells as well as its toxicity toward normal human lung fibroblast. Cell viability, cell migration, and invasion were measured by thiazolyl blue tetrazolium bromide (MTT) assay, wound healing assay, and Transwell chamber assay, respectively. The expression of metastasis-related genes was assessed with quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Actin and vimentin filaments were examined under the fluorescence microscope. The combination of FIS and PTX significantly reduced cancer cell migration and invasion, at least partially, through a marked rearrangement of actin and vimentin cytoskeleton and the modulation of metastasis-related genes. Most of these effects of the combination treatment were significantly greater than those of individual agents. Paclitaxel alone was even more toxic to normal cells than the combination of this drug with the flavonoid, suggesting that FIS may provide some protection against PTX-mediated cytotoxicity. The combination of FIS and PTX is expected to have a synergistic anticancer efficacy and a significant potential for the treatment of NSCLC, however, further in vitro and in vivo studies are required to confirm this preliminary evidence.
... The reactive oxygen species (ROS)-inducing effect of scutellaria (caption on next page) total flavones on different cancer cell types has been documented, and ROS is a potent activator of the mitochondria mediated intrinsic apoptosis pathway [9,22,23]. Mitochondrial respiratory chain and the membrane-associated NADPH oxidase are the two-major producer of ROS in mammalian cells [24]. We therefore evaluated general ROS production in MM cells and viable CBL cells treated with scutellarein. ...
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Objectives Scutellarein is a flavonoid monomer found in traditional Chinese medicine such as Scutellaria barbata. This study aimed to investigate the cytotoxic effect of scutellarein treatment on multiple myeloma (MM) cells. Methods circulating B lymphocytes (CBL) isolated from healthy donors’ peripheral blood served as control for MM.1R and IM-9 MM cells. CLB and MM cells were treated with various concentrations of scutellarein before their cell viability and apoptosis being evaluated. Nude mice burdened with MM xenograft tumor were intravenously injected with different concentrations of scutellarein, and their tumor burden change were monitored. Apoptosis of MM cells or CBL after scutellarein treatment was assayed by measuring caspase-3, -8 and -9 activities. FADD or APAF1 gene knockdown in MM cells was achieved by lentiviral transfection. Amount of Cytochrome C in cytosol or mitochondria as well as that of Bax and Bcl-2 protein were evaluated by Western blot. Mitochondria-induced apoptosis was assayed by measuring mitochondrial membrane potential change. Production of general reactive oxygen species and mitochondrial superoxide in MM or CBL was detected after scutellarein treatment, which was reduced by MitoTEMPO or apocynin treatment, respectively. Results Scutellarein treatment showed potent cytotoxicity on MM cells but not on viable CBL, and intravenous injection of scutellarein significantly reduced MM xenograft tumor burden in nude mice. Scutellarein treatment in MM cells activated the mitochondrial-mediated intrinsic apoptosis pathway by increasing the production of mitochondrial superoxide, which was reduced to ROS by NADPH, but this effect was weakened in healthy CBL. Co-treatment with scutellarein synergized with bortezomib in inducing apoptosis in MM cells in vitro and in reducing tumor volume in MM xenografted nude mice. Conclusions Scutellarein induced mitochondrial-mediated intrinsic apoptosis selectively on malignant cells comparing to healthy cells.
... Huang et al. found that the expression of lncRNA NR2F1-AS1 was up-regulated in chemo-resistant hepatocellular carcinoma and could promote the invasion, migration and drug-resistant in vitro [32]. Jiang et al. demonstrated that dietary supplements could suppress metastatic behavior of prostate cancer cells by down-regulating the expression of NR2F1 [33]. ...
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Background: Salivary adenoid cystic carcinoma (SACC) can recur after removal of the primary tumor and treatment, where they can keep no clinical symptoms and dormant state for 10-15 years. NR2F1 has been demonstrated to regulate the tumor cell dormancy in various malignant tumors and has a potential impact on recurrence and metastasis of carcinoma. However, the role and significance of NR2F1 in SACC dormancy still remain unknown. Methods: A total number of 59 patients with a diagnosis of SACC were included to detected expression of NR2F1, Ki-67 by immunohistochemical (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling (TUNEL). Fisher's exact test was used to examine the NR2F1 expression and clinicopathologic parameters of SACC. In vitro, SACC cell lines were transfected NR2F1 and knockdown NR2F1 respectively. CCK-8, flow cytometry, wound healing assay and transwell invasion determined SACC cell proliferation, apoptosis, cell cycle, migration and invasion respectively. Chromatin immunoprecipitation (ChIP) assays were utilized to demonstrate the potential role of NR2F1 in SACC invasion via CXCL12/CXCR4 axis. In vivo, xenografts of nude mice via subcutaneous injection or tail vein injection were used to testify the results in vitro. Results: Among the 59 patients with SACC, 23.73% (14/59) were positive to NR2F1 expression, a lower rate of expression compared with 60% (6/10) in normal salivary gland samples. NR2F1 was correlated with metastasis, relapse and dormancy of SACC. SACC cells with transfected NR2F1 remained dormant, as well as enhanced invasion and metastasis. Knockdown of NR2F1 via siRNA after NR2F1 overexpression restored the proliferation and the cell number in G2/M phases, and reduced the abilities of migration and invasion. In addition, NR2F1 promoted the expression of CXCL12 and CXCR4, and overexpression of CXCL12 at least partly rescued the proliferation, migration, and invasion activities induced by NR2F1 silencing. Conclusions: NR2F1 may be an underlying mechanism of SACC recurrence and metastasis via regulating tumor cell dormancy through CXCL12/CXCR4 pathway.
... Similarly to MMP-9, inhibi-tion of uPA results in inhibition of cancer cell implantation, invasion and metastasis (8,13,(23)(24)(25). EGCG inhibits expression of uPA most likely by suppression of NFκB (26,27) and urokinase activity (13)(14)(15)27). Consequently, the inhibition of MMP and uPA expression and/or activity by EGCG signifies potential novel therapeutic strategies for the treatment of cancer patients. ...
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The aim of this study was to determine the efficacy of epigallocatechin-3-gallate (EGCG) (Polyphenon E®) in comparison with mitomycin C (MMC) to prevent tumor cell implantation/growth in an animal model of superficial bladder cancer and search for possible mechanism(s) of action. Female Fisher 344 rats were used to study the effects of EGCG and mitomycin C for the prevention of transitional cell tumor implantation (AY-27). Twenty rats served as a control, tumor implantation and saline wash only. Sixty rats were treated with EGCG (100, 200 and 400 µM) intravesically for 60 or 120 min after tumor implantation. Thirty other rats were divided equally and pretreated with 400 µM EGCG or saline for 120 min before tumor initiation. In a separate series of experiments, 30 rats were treated 2 weeks after tumor initiation with saline or EGCG (400 µM). In a different experiment 39 rats were treated with: saline (n=10) EGCG (n=9) 400 µM, MMC (n=10) 0.5 µM, MMC (n=10) 400 µM. Rats were sacrificed 3 weeks following treatment. Gross and histological analyses were performed on the bladders. EGCG and mitomycin C prevented intravesical tumor growth in a concentration- and time-dependent manner. EGCG pretreatment or treatment 2 weeks post tumor implantation did not have therapeutic effects. Molecular modeling suggests that EGCG inhibits urokinase and matrix metalloproteinase-9. EGCG prevents intravesical tumor implantation/growth with a slightly better efficacy than mitomycin C in this experimental model. The data suggest that EGCG lowers proteolytic activity and lowers probability of cancer cell implantation rather than direct cancer cell killing.
... After 12 months, the hyperplasia-caused urination and bladder problems subsided and conspicuous progress in urinary flow was observed. Jiang et al. [28] showed that ProstaCaid TM treatment (a polyherbal preparation with pumpkin seed as an ingredient) resulted in the inhibition of cell proliferation of the highly invasive human hormoneindependent prostate cancer PC-3 cells in a dose-and timedependent manner. DNA-microarray analysis demonstrated that it inhibited the proliferation of cancerous cells through the modulation in expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes. ...
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The seeds of pumpkin (Cucurbita sp.) are gen- erally considered to be agro-industrial wastes and dis- carded. In some parts of the world, the seeds are consumed raw, roasted or cooked, but only at the domestic scale. With the discovery of their richness in protein, fibres, minerals, polyunsaturated fatty acids and phytosterols, they are being regarded valuable for the food industry. The attention of food technologists has resulted in their foray into the commercial food sector. Food companies are experimenting with their incorporation into a slew of savouries and con- sumers are showing interest in them. Also, their beneficial effects on blood glucose level, immunity, cholesterol, liver, prostate gland, bladder, depression, learning disabilities and parasite inhibition are being validated. The conversion of these agro-wastes into value-added ingredients is likely to be a big step towards the global sustainability efforts; thus, it deserves more investigation. This review furnishes an updated account of this emerging nutraceutical.
... Thus, the need is increasing for further pharmacological studies and clinical trials on these biological impacts of pumpkin seed oil. ProstaCaidTM ® , a polyherbal medication, includes pumpkin seed extract as a constituent and contributes to suppress the cell proliferation of greatly invading human hormone-independent prostate cancer (PC-3) cells in a time-and dose-dependent method [62]. Experimental studies stated that β-sitosterol, a phytosterol included in pumpkin seeds, may consistently recover the urinary symptoms linked with prostate enlargement [63]. ...
... Other Chinese herbs have also been associated with anti-tumor effects [95–101]. Two studies have shown that American ginseng (Panax quinquefolius L.) extracts can inhibit tumor growth in HCT-116 [75] and MCF-7 cells [76]. ...
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Meridians, acupoints, and Chinese herbs are important components of traditional Chinese medicine (TCM). They have been used for disease treatment and prevention and as alternative and complementary therapies. Systems biology integrates omics data, such as transcriptional, proteomic, and metabolomics data, in order to obtain a more global and complete picture of biological activity. To further understand the existence and functions of the three components above, we reviewed relevant research in the systems biology literature and found many recent studies that indicate the value of acupuncture and Chinese herbs. Acupuncture is useful in pain moderation and relieves various symptoms arising from acute spinal cord injury and acute ischemic stroke. Moreover, Chinese herbal extracts have been linked to wound repair, the alleviation of postmenopausal osteoporosis severity, and anti-tumor effects, among others. Different acupoints, variations in treatment duration, and herbal extracts can be used to alleviate various symptoms and conditions and to regulate biological pathways by altering gene and protein expression. Our paper demonstrates how systems biology has helped to establish a platform for investigating the efficacy of TCM in treating different diseases and improving treatment strategies.
... ProstaCaid™ (PC) is a polybotanical dietary supplement which inhibits aberrant cell proliferation, induce apoptosis and inhibits invasiveness of a variety of prostate cancer cells, respectively (6,7). PC contains mycelium from Asian medicinal mushrooms (Ganoderma lucidum, Coriolus versicolor and Phellinus linteus), which separately demonstrated anticancer activities against prostate cancer cells in vitro and in animal experiments (8)(9)(10)(11)(12)(13). ...
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We have recently demonstrated that the dietary supplement ProstaCaid (PC) inhibits growth and invasive behavior of PC-3 human prostate cancer cells in vitro. In the present study, we evaluated toxicity and whether PC suppresses growth of prostate cancer in a xenograft model of human prostate cancer cells implanted in mice. Here, we show that an oral administration of PC (100, 200 and 400 mg/kg) did not affect body weight or activity of liver enzymes (ALT, AST) and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. In addition, PC treatment resulted in the inhibition of tumor volumes (1024.6 ± 378.6 vs. 749.3 ± 234.3, P<0.001) in a xenograft model of prostate cancer with human hormone refractory (independent) PC-3 prostate cancer cells. Moreover, qRT-PCR analysis demonstrated significant upregulation of expression of CDKN1A (p21) and inhibition of expression of IGF2, NR2F2 and PLAU (uPA) genes by an oral administration of PC in prostate cancer xenografts. Our study demonstrates that the concentrations of the dietary supplement ProstaCaid tested did not show signs of toxicity, and its oral application has significant anticancer activity in vivo and can be considered as an alternative treatment for prostate cancer patients.
... In addition to acting as a powerful antioxidant, EGCG also acts as an antiangiogenic factor, promotes apoptosis, and induces cell growth arrest via cell cycle regulatory proteins; it also activates killer caspases, and suppresses oncogenic transcription factors [6]. It has been shown that EGCG reduces PC3 prostate cancer growth via MEK-independent ERK1/2 activation [7], inhibits proliferation via alteration of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes [8]. In another androgen-independent prostate cancer cell line (DU 145) EGCG alters genes involved in the functions of transcription, RNA processing, protein folding, phosphorylation, protein degradation, cell motility, and ion transport [9], and induces mRNA expression of interleukin (IL)-6, IL-8, CXCL1, IP-10, CCL5, and transforming growth factor β (TGF-β) [10]. ...
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Structurally related lanostane-type triterpenes, ganoderic acid A, F and H (GA-A, GA-F, GA-H), were identified in an oriental medicinal mushroom Ganoderma lucidum. In the present study we evaluated the effect of GA-A, GA-H and GA-F on highly invasive human breast cancer cells. We showed that GA-A and GA-H suppressed growth (cell proliferation and colony formation) and invasive behavior (adhesion, migration and invasion) of MDA-MB-231 cells. Our results suggest that GA-A and GA-H mediate their biological effects through the inhibition of transcription factors AP-1 and NF-kappa B, resulting in the down-regulation of expression of Cdk4 and the suppression of secretion of uPA, respectively. Furthermore, the activity of ganoderic acids is linked to the hydroxylation in the position 7 and 15 (GA-A) and 3 (GA-H) in their triterpene lanostane structure. In conclusion, hydroxylated triterpenes from G. lucidum could be promising natural agents for the therapy of invasive breast cancers.
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Mushrooms are an integral part of Traditional Chinese Medicine (TCM), and have been used for millennia to prevent or treat a variety of diseases Currently mushrooms or their extracts are used globally in the form of dietary supplements In the present study we have evaluated the anticancer effects of the dietary supplement MycoPhyto (R) Complex (MC), a novel medicinal mushroom blend which consists of a blend of mushroom mycelia from the species Agaricus blazei, Cordyceps sinensis, Coriolus verstcolor, Ganoderma lucidum, Grifola frondosa and Polyporus umbellatus, and beta-1,3-glucan isolated from the yeast, Saccharomyces cerevisiae Here, we show that MC demonstrates cytostatic effects through the inhibition of cell proliferation and cell cycle arrest at the G2/M phase of highly invasive human breast cancer cells MDA-MB-231 DNA-microarray analysis revealed that MC inhibits expression of cell cycle regulatory genes (ANAPC2, ANAPC2 BIRC5, Cyclin B1 Cychn H, CDC20 CDK2, CKS1B Cullin 1 E2F1 KPNA2 PKMYT1 and TFDP1) Moreover, MC also suppresses the metastatic behavior of MDA-MB-231 by the inhibition of cell adhesion, cell migration and cell invasion The potency of MC to inhibit invasiveness of breast cancer cells is linked to the suppression of secretion of the urokinase plasminogen activator (uPA) from MDA-MB-231 cells In conclusion, the MC dietary supplement could have potential therapeutic value in the treatment of invasive human breast cancer
Article
Ganoderma, highly ranked in Oriental traditional medicine, has been used as a remedy for many types of chronic diseases, including hepatopathy, type II diabetes, neurasthenia, hypertension, and cancer. Various polysaccharides (i.e., β-D-glucans and glycoproteins) and triterpenoids are the major active constituents present in Ganoderma. In vitro and animal studies have indicated that Ganoderma exhibits cancer-preventive and anticancer activity. Data from a clinical study in cancer patients showed Ganopoly, a crude Ganoderma polysaccharide extract, enhanced host immune function, including increased activity of effector cells such as T lymphocytes, macrophages, and natural killer cells, despite the lack of striking objective antitumor activity. Several clinical studies revealed that treatment of prostate cancer patients with the Ganoderma-containing PC-SPES (a mixture of eight herbal extracts) gave a significant decrease in the prostate-specific antigen levels, which compares favorably with second-line hormonal therapy that has agents such as estrogens and ketoconazole. Currently available data from numerous in vitro and in vivo studies suggest that the cancer-preventive and tumoricidal properties of Ganoderma might be ascribed to its antioxidative and radical-scavenging effects, enhancement of host immune function, induction of cell-cycle arrest and apoptosis, and other biological effects. Although Ganoderma may represent a practical and promising approach for cancer prevention and cancer treatment, further experimental, epidemiological, and clinical studies are needed to identify unrevealed molecular targets, resolve the relationship between Ganoderma intake and cancer risks, and explore the optimum dosing, efficacy, and safety, alone or in combination with chemotherapy/radiotherapy.
Article
Prostate cancer results from complex interactions among genetic, endocrine, and environmental factors. Understanding genetic risk factors that contribute to the occurrence of prostate cancer is crucial to design both preventative and therapeutic strategies and to identify at-risk individuals. This knowledge could reduce the incidence of and death from this disease. The primary objective of this grant is to investigate changes in genes that directly and indirectly regulate levels of male hormones, which in turn, affect prostate cell growth, and may ultimately cause cancer. In this past year, we have performed genotyping for variants in INS and IRS2 to analyze in conjunction with the IRS1 and IGF1 variant genotypes to look at main effects and gene x gene interactions. In addition, we investigated haplotypes in IGFBP1 and SHBG in order to assess the association with variation across the entire gene. Statistical methods were used to analyze the association of these genes with occurrence of prostate cancer, age at diagnosis and disease aggressiveness. The IRS1 variant was associated with a 2.7 fold increased risk of prostate cancer.
Article
Alternative cancer treatment with nutritional/dietary supplements containing a wide variety of herbal products is on the rise in Western countries. Recent epidemiological studies have suggested that mushrooms may prevent against different types of cancers. Phellinus linteus is a well-known Oriental medicinal fungus with a variety of biological activities, including immunomodulatory or direct antitumor activities. The activity of P. linteus and its extracts is associated with the presence of polysaccharides, their peptide/protein complexes and other low molecular weight complexes. Polysaccharide fractions isolated from P. linteus were found to be related to the increased activity of immune cells such as the production of cytokines by macrophages and B-cells or the increased cytotoxic activity of natural killer cells. Moreover, P. linteus was found to modulate the expression or activity of various genes involved in cell proliferation, apoptosis, angiogenesis, invasive behavior and chemoprevention. Finally, P. linteus extracts demonstrated tumor regression in three independent case reports, suggesting that an extract from P. linteus or a dietary supplement based on the extract from P. linteus may have potential use for the alternative treatment of cancer.
Article
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010. Overall cancer incidence rates decreased in the most recent time period in both men (1.3% per year from 2000 to 2006) and women (0.5% per year from 1998 to 2006), largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and 2 major cancer sites in women (breast and colorectum). This decrease occurred in all racial/ethnic groups in both men and women with the exception of American Indian/Alaska Native women, in whom rates were stable. Among men, death rates for all races combined decreased by 21.0% between 1990 and 2006, with decreases in lung, prostate, and colorectal cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2006 decreased by 12.3%, with decreases in breast and colorectal cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
Article
Resveratrol exhibits potential anti-carcinogenic activities. Heme oxygenase-1 (HO-1) is involved in angiogenesis and tumor metastasis. Matrix metalloproteinases (MMPs) are key enzymes in the degradation of extracellular matrix, and their expression may be dysregulated in lung cancer metastasis. In this study, we investigated the anti-invasive mechanism of resveratrol in lung cancer cells. HO-1 was shown to be elevated (approximately 4.7-fold) in lung cancer tumor samples as compared with matched normal tissues. After treatment of lung adenocarcinoma cell line A549 cells with resveratrol (50 microM) for 24 h, the migratory and invasive abilities (38 and 30% inhibition, respectively) of A549 cells were significantly reduced. Resveratrol significantly inhibited HO-1-mediated MMP-9 (35% inhibition) and MMP-2 (28% inhibition) expression in lung cancer cells. Nuclear factor (NF)-kappaB inhibitor induced a marked reduction in MMP-9 and MMP-2 expression, suggesting NF-kappaB pathway could play an important role. Furthermore, HO-1 inhibition and silencing significantly suppressed MMPs and invasion of lung cancer cells. Our results suggest that resveratrol inhibited HO-1 and subsequently MMP-9 and MMP-2 expression in lung cancer cells. The inhibitory effects of resveratrol on MMP expression and invasion of lung cancer cells are, in part, associated with the HO-1-mediated NF-kappaB pathway.
Article
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is also highly metastatic. Metastasis is considered to be the major cause of death in cancer patients. Resveratrol (3,5,4'-trihydroxystilbene) and related analogues have been reported as candidates to prevent cancer growth and invasion. The bioactivity of resveratrol-related analogues could be altered due to the presence and positioning of methoxy groups on the basic resveratrol chemical structure. This study investigated the effects and mechanism of action of resveratrol and its methoxy analogues on invasion of human hepatocarcinoma cells. The migratory and invasive abilities of phorbol 12-myristate 13-acetate (PMA)-treated HepG2 and PMA-untreated Hep3B cells were both reduced in a dose-dependent manner by treatment with resveratrol and 3,5,4'-trimethoxy-trans-stilbene (MR-3). Upon incubation of PMA-treated HepG2 cells with resveratrol (0-50 microM) or MR-3 (0-50 microM), the MMP-9 activity decreased but TIMP-1 protein increased in a dose-dependent manner. With resveratrol (0-50 microM) or MR-3 (0-1 microM) treatment on PMA-untreated Hep3B cells, both of the MMP-9 and MMP-2 activities decreased but TIMP-2 protein increased in a dose-dependent manner. These results suggest that resveratrol and its related methoxy analogue MR-3 might exert anti-invasive activity against hepatoma cells through regulation of MMP-2, MMP-9, TIMP-1, and TIMP-2. Further analysis with semiquantitative RT-PCR showed that the regulation of MMP-9 and TIMP-2 expressions by resveratrol and MR-3 in hepatoma cells may be on the transcriptional level but on the translational or post-translational level for TIMP-1.
Article
Accumulating data clearly indicate that induction of apoptosis is an important event for chemoprevention of cancer by naturally occurring dietary agents. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by pro-apoptotic receptor signals at the cellular surface; and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. This process is strictly controlled in response to integrity of pro-death signaling and plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. For chemoprevention studies, prostate cancer (PCa) represents an ideal disease due to its long latency, its high incidence, tumor marker availability, and identifiable preneoplastic lesions and risk groups. In this article, we highlight the studies of various apoptosis-inducing dietary compounds for prevention of PCa in vitro in cell culture, in preclinical studies in animals, and in human clinical trials.
Article
PSK, a protein-bound polysaccharide obtained from cultured mycelia of Coriolus versicolor in basidiomycetes, is a biological response modifier, diverse operations of which include an antitumor action. We have previously reviewed recent research which had demonstrated that in animals, PSK has a preventive effect on chemical carcinogen-induced, radiation-induced, and spontaneously developed carcinogenesis (Kobayashi et al., Cancer Epidemiol., Biomarkers & Prev., 2: 271-276, 1993). We now focus on the effects of PSK once the progression of carcinogenesis has begun, and review what is now known of the preventive action of PSK on cancer metastasis. Recent research reports that PSK suppresses pulmonary metastasis of methylcholanthrene-induced sarcomas, human prostate cancer DU145M, and lymphatic metastasis of mouse leukemia P388, and that it has prolonged the survival period in spontaneous metastasis models. PSK also suppresses the metastasis of rat hepatoma AH60C, mouse colon cancer colon 26, and mouse leukemia RL male 1 in artificial metastasis models. PSK influences the steps of cancer metastasis in a number of ways: (a) by suppression of intravasation through the inhibition of tumor invasion, adhesion and production of cell matrix-degrading enzymes; (b) by suppression of tumor cell attachment to endothelial cells through the inhibition of tumor cell-induced platelet aggregation; (c) by suppression of tumor cell migration after extravasation through the inhibition of tumor cell motility; and (d) by suppression of tumor growth after extravasation through the inhibition of angiogenesis, the modulation of cytokine production, and the augmentation of effector cell functions. In addition, PSK has suppressed the malignant progression of mouse tumor cells through superoxide trapping.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Mammalian cell-cycle control by antimitogenic signals involves p21Cip1/WAF1 (refs 1-4), p27Kip1 (refs 5, 6) and p57Kip2 (refs 7, 8), a family of proteins that bind to and inhibit cyclin-dependent kinases (CDKs) required for initiation of S phase. The protein p21 also binds to the DNA polymerase delta processivity factor, proliferating-cell nuclear antigen (PCNA), and inhibits in vitro PCNA-dependent DNA replication. The CDK and PCNA inhibitory activities of p21 are shown here to be functionally independent and to reside in separate protein domains. The PCNA binding and inhibitory activities, which are not observed with p27 or p57, reside in the C-terminal domain of p21, whereas the CDK inhibitory activity resides in the conserved N-terminal domains of these proteins. When separately overexpressed in mammalian cells, the CDK and PCNA inhibitory domains prevent DNA replication, demonstrating a dual function of p21 as a cell-cycle inhibitor in vivo.
Article
During this year there will be approximately 30 thousand deaths due to prostatic cancer in the United States (1). This mortality rate makes prostatic cancer the second commonest fatal tumor in males of all ages in America (1). Besides a high annual mortality rate, prostatic cancer is now the most commonly diagnosed malignancy in males of all ages in the United States (1). These high annual incidence rates translate into the human reality that one of every 11 American white male will eventually develop clinical prostatic cancer during their lifetime (2). Rates for American black males are even higher such that the lifetime risk for cancer is one out of every 10 (3). In addition, the annual incidence rate of clinical prostatic cancer has increased steadily since 1930’s to the present time (4).
RPSP, a refined polysaccharide peptide fraction isolated by fast performance liquid chromatography (FPLC) from the crude powder of total peptide-bound polysaccharides of cultivated Coriolus versicolor Cov-1 dose-dependently inhibited the proliferation of a human hepatoma cell line (HEPG2). The effective dose causing 50% inhibition following 3-day exposure to RPSP was 243 +/- 36 micrograms/ml for HEPG2. However, little or no inhibitory effects were detected in normal human foetal hepatocytes. On the other hand, in the pretreatment group, in which RPSP was administered i.p. for two weeks before sarcoma 180 inoculation in nude mice, the incidence of tumor growth was less (2 out of 5 mice) than that of the control group (all 5 mice). The tumor size of the control group was about 3-5 times bigger than that of the pretreatment group. In tumor-bearing nude mice, 5 days after sarcoma 180 inoculation, i.v. administration of RPSP significantly suppressed the growth of tumor mass. The inhibition rate was 93.6% on day 13. Furthermore, administration of RPSP did not cause any pathological lesions in vital organs of rabbits such as heart, liver, spleen, lung and kidney. In conclusion, these results indicate that RPSP acts by directly suppressing tumor cell growth in vitro and the prevention of in vivo growth of tumor mass is probably mediated also via its immunomodulating effects.
Article
In the last three decades, numerous polysaccharides and polysaccharide-protein complexes have been isolated from mushrooms and used as a source of therapeutic agents. The most promising biopharmacological activities of these biopolymers are their immunomodulation and anti-cancer effects. They are mainly present as glucans with different types of glycosidic linkages such as (1-->3), (1-->6)-beta-glucans and (1-->3)-alpha-glucans, and as true herteroglycans, while others mostly bind to protein residues as polysaccharide-protein complexes. Three antitumor mushroom polysaccharides, i.e. lentinan, schizophyllan and protein-bound polysaccharide (PSK, Krestin), isolated respectively, from Lentinus edodes, Schizophyllum commune and Coriolus versicolor, have become large market items in Japan. Lentinan and schizophyllan are pure beta-glucans, whereas PSK is a protein-bound beta-glucan. A polysaccharide peptide (PSP), isolated from a strain of Coriolus versicolor in China, has also been widely used as an anti-cancer and immunomodulatory agent. Although the mechansim of their antitumor action is still not completely clear, these polysaccharides and polysaccharide-protein complexes are suggested to enhance cell-mediated immune responses in vivo and in vitro and act as biological response modifiers. Potentiation of the host defense system may result in the activation of many kinds of immune cells that are vitally important for the maintenance of homeostasis. Polysaccharides or polysaccharide-protein complexes are considered as multi-cytokine inducers that are able to induce gene expression of vaious immunomodulatory cytokines and cytokine receptors. Some interesting studies focus on investigation of the relationship between their structure and antitumor activity, elucidation of their antitumor mechanism at the molecular level, and improvement of their various biological activities by chemical modifications.
Article
Prostate cancer (PCA) is the most common invasive malignancy and leading cause (after lung) of cancer deaths in males. Since PCA is initially androgen-dependent, strategies are targeted toward androgen depletion for its control. However, tumor re-growth mostly occurs following this modality, and is androgen-independent. A loss of functional androgen receptor and an enhanced expression of growth factor receptors (e.g. erbB family members) and associated ligands have been shown to be the causal genetic events in PCA progression. These genetic alterations lead to an epigenetic mechanism where a feed-back autocrine loop between membrane receptor (e.g. epidermal growth factor receptor [erbB1] and associated ligand (e.g. transforming growth factor-alpha) results in an enhanced activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) as an essential component of the uncontrolled growth of PCA at an advanced and androgen-independent stage. Together, we rationalized that inhibiting these epigenetic events would be useful in controlling advanced PCA growth. Dietary polyphenolic flavonoids and isoflavones are being studied extensively as cancer-preventive and interventive agents. Therefore, we focused our attention on silymarin, genistein, and epigallocatechin 3-gallate (EGCG), present in milk thistle, soy beans, and green tea, respectively. The effect of these agents was assessed on the erbB1-Shc-ERK1/2 signal transduction pathway, cell cycle regulatory molecules, and cell growth and death. In androgen-independent human prostate carcinoma DU145 cells, silymarin, genistein, and EGCG resulted in a significant to complete inhibition of transforming growth factor-alpha-caused activation of membrane receptor erbB1 followed by inhibition of downstream cytoplasmic signaling target Shc activation and a decrease in its binding with erbB1, without an alteration in their protein expression. Silymarin and genistein also inhibited ERK1/2 activation, suggesting that these agents impair the activation of erbB1-Shc-ERK1/2 signaling in DU145 cells. In the case of EGCG, a further increase in ERK1/2 activation was observed that was related to its pro-oxidant and apoptotic activities. Silymarin, genistein, and EGCG also resulted in a significant induction of Cip1/p21 and Kip1/p27 and a decrease in cyclin-dependent kinase (CDK) 4, but a moderate inhibition of CDK2, cyclin D1, and cyclin E was observed. An enhanced level of Cip1/p21 and Kip1/27 also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein, and EGCG also resulted in strong cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein also showed cell death. A more profound cytotoxic effect was observed in the case of EGCG, with strong cell death at lower doses and complete loss of viability at higher doses. Together, these results suggest that cell signaling and regulators of cell cycle are potential epigenetic molecular targets for prostate cancer prevention by dietary agents. More studies, therefore, are needed with these agents to explore their anticarcinogenic potential against human prostate cancer.
Article
Resveratrol is a naturally occurring polyphenol with cancer chemopreventive properties. The objective of the current study was to investigate the effect of resveratrol on the human colonic adenocarcinoma cell line Caco-2. The compound inhibited cell growth and proliferation of Caco-2 cells in a dose-dependent manner (12.5-200 micromol/L) as assessed by crystal violet assay, [(3)H]thymidine and [(14)C]leucine incorporation. Furthermore, apoptosis was determined by measuring caspase-3 activity, which increased significantly after 24 and 48 h of treatment with 200 micromol/L resveratrol. Perturbed cell cycle progression from the S to G2 phase was observed for concentrations up to 50 micromol/L, whereas higher concentrations led to reversal of the S phase arrest. These effects were specific for resveratrol; they were not observed after incubation with the stilbene analogs stilbenemethanol and rhapontin. Levels of cyclin D1 and cyclin-dependent kinase (cdk) 4 proteins were decreased, as revealed by immunoblotting. In addition, resveratrol enhanced the expression of cyclin E and cyclin A. The protein levels of cdk2, cdk6 and proliferating cell nuclear antigen were unaffected. Similar results were obtained for the colon carcinoma cell line HCT-116, indicating that cell cycle inhibition by resveratrol is independent of cyclooxygenase inhibition. The phosphorylation state of the retinoblastoma protein in Caco-2 cells was shifted from hyperphosphorylated to hypophosphorylated at 200 micromol/L, which may account for reversal of the S phase block at concentrations exceeding 50 micromol/L. These findings suggest that resveratrol exerts chemopreventive effects on colonic cancer cells by inhibition of the cell cycle.
Article
Three new lanostante-type triterpene aldehydes, named lucialdehydes A-C (1-3), were isolated from the fruiting bodies of Ganoderma lucidum, together with ganodermanonol (4), ganodermadiol (5), ganodermanondiol (6), ganodermanontriol (7), ganoderic acid A (8), ganoderic acid B8 (9), and ganoderic acid C1 (10). The structures of the new triterpenes were determined as (24E)-3 beta-hydroxy-5 alpha-lanosta-7,9(11),24-trien-26-al (1), (24E)-3,7-dioxo-5 alpha-lanosta-8,24-dien-26-al (2), and (24E)-3 beta-hydroxy-7-oxo-5 alpha-lanosta-8,24-dien-26-al (3), respectively, by spectroscopic means. The cytotoxicity of the compounds isolated from the ganoderma mushroom was tested in vitro against Lewis lung carcinoma (LLC), T-47D, Sarcoma 180, and Meth-A tumor cell lines. Lucialdehydes B, C (2, 3), ganodermanonol (4) and ganodermanondiol (6) showed cytotoxic effects on tested tumor cells. Of the compounds, lucialdehyde C (3) exhibited the most potent cytotoxicity against LLC, T-47D, Sarcoma 180, and Meth-A tumor cells with ED(50) values of 10.7, 4.7, 7.1, and 3.8 microg/ml, respectively.
Article
A dried powder from basidiomycetous fungi, Ganoderma lucidum, has been used in East Asia in therapies for several different diseases, including cancer. However, the molecular mechanisms involved in the biological actions of Ganoderma are not well understood. We have recently demonstrated that phosphatidylinositol 3-kinase (PI 3-kinase) and nuclear factor-kappaB (NF-kappaB) regulate motility of highly invasive human breast cancer cells by the secretion of urokinase-type plasminogen activator (uPA). In this study, we investigated the effect of G. lucidum on highly invasive breast and prostate cancer cells. Here we show that spores or dried fruiting body of G. lucidum inhibit constitutively active transcription factors AP-1 and NF-kappaB in breast MDA-MB-231 and prostate PC-3 cancer cells. Furthermore, Ganoderma inhibition of expression of uPA and uPA receptor (uPAR), as well secretion of uPA, resulted in the suppression of the migration of MDA-MB-231 and PC-3 cells. Our data suggest that spores and unpurified fruiting body of G. lucidum inhibit invasion of breast and prostate cancer cells by a common mechanism and could have potential therapeutic use for cancer treatment.
Article
In a recent study on head and neck squamous cell carcinoma (HNSCC) cells we found that epigallocatechin-3-gallate (EGCG), a major biologically active component of green tea, inhibited activation of the epidermal growth factor receptor (EGFR) and related signaling pathways. Since activation of EGFR signaling pathways is associated with angiogenesis, we examined the effects of EGCG on vascular endothelial growth factor (VEGF) production by YCU-H891 HNSCC and MDA-MB-231 breast carcinoma cell lines, because we found that both of these cell lines display autocrine activation of transforming growth factor-alpha (TGF-alpha)/EGFR signaling and produce high levels of VEGF. Treatment with EGCG inhibited the constitutive activation of the EGFR, Stat3, and Akt in both cell lines. These changes were associated with inhibition of VEGF promoter activity and cellular production of VEGF. Mechanistic studies indicated that inhibition of Stat3, but not mitogen-activated protein kinase kinase (MEK)1 or phosphatidylinositol 3'-kinase (PI3K), significantly decreased VEGF promoter activity. However, the inhibitory effects of a dominant negative Stat3 on VEGF expression was not as strong as that produced by EGCG. An analysis of alternative pathways indicated that EGCG strongly inhibited the constitutive activation of NF-kappa B in both cell lines, and an NF-kappa B inhibitor strongly inhibited VEGF production. These results suggest that EGCG inhibits VEGF production by inhibiting both the constitutive activation of Stat3 and NF-kappa B, but not extracellular-signal-regulated kinase (ERK) or Akt, in these cells. Therefore, EGCG may be useful in treating HNSCC and breast carcinoma because it can exert both antiproliferative and antiangiogenic activities.
Article
The incidence of prostate cancer in Western countries continues to rise. Whilst opinion remains divided on the best treatment for localized disease, intervention for metastatic, hormone-independent cancer remains extremely limited. The concept of chemoprevention is gaining popularity as an effective means of reducing the burden of prostate cancer on the population, and many compounds with putative chemopreventive activity are currently under investigation. Resveratrol is a plant-derived polyphenolic compound which has a wide spectrum of biological activity. It has anti-oxidant and anti-inflammatory properties, and may induce apoptosis as well as modulate the function of the androgen receptor in prostate cancer cell lines. Further studies to evaluate the use of this compound as a chemopreventive agent in prostate cancer are warranted.
Article
Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, is a promising chemopreventive agent. We recently showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells [Proc. Natl. Acad. Sci. USA 98 (2001) 10350]. Earlier, we showed that EGCG causes a G0/G1 phase cell cycle arrest and apoptosis of both androgen-sensitive LNCaP and androgen-insensitive DU145 human prostate carcinoma cells, irrespective of p53 status [Toxicol. Appl. Pharmacol. 164 (2000) 82]. Here, we provide molecular understanding of this effect. We tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. As shown by immunoblot analysis, EGCG treatment of LNCaP and DU145 cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18, (ii) down-modulation of the protein expression of cyclin D1, cyclin E, cdk2, cdk4, and cdk6, but not of cyclin D2, (iii) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27, and (iv) decrease in the binding of cyclin E toward cdk2. Taken together, our results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG.
Article
The use of herbal medicine is a common practice among Chinese women with breast cancer. Yunzhi (Voriolus versicolor), a substance that is regarded as a biological response modifier, is frequently used. The aim of the present study is to evaluate the anti-proliferative action of, Yunzhi, polysaccharide peptide (PSP), on breast cancer cells. Breast cancer cells (MDA-MB-231) were cultured with and without PSP for 7 days. Cell growth at 24, 72, 120 and 168 hours was measured by Cell Proliferation Reagent (WST-1). Cells treated with PSP were found to have a significant reduction in cell proliferation as compared to controls after 72 hours of incubation. This lasted for 168 hours. When the effect of PSP on apoptosis was studied by the TdT-mediated X-dUTP nick end-labeling (TUNEL) assay, we found that PSP had a significant effect upon apoptosis from 24 hours onward. Immunostaining showed that PSP increased p21 expression and decreased cyclin D1 expression. In conclusion, PSP is effective in inhibiting cell proliferation through apoptosis. The mechanism for the apoptosis may be through up-regulation of p21 and down-regulation of cyclin D1.
Article
Prostate cancer is the most frequent cancer among men in most developed countries, yet little is known about its causes. Older age, African ancestry and a positive family history of prostate cancer have long been recognized as important risk factors. The evidence that genetics probably plays a critical role is based on a variety of study designs, including case-control, cohort, twin and family-based, all of which are reviewed in detail. The search for prostate cancer susceptibility genes by linkage studies offered early hope that finding genes would be as 'easy' as finding genes for breast cancer and colon cancer susceptibilities. However, this hope has been dampened by the difficulty of replicating promising regions of linkage. This review provides updates on recent developments, and a broad view of the disparate findings from different linkage studies. Early linkage results have provided targeted candidate regions for prostate cancer susceptibility loci, including HPC1 on chromosome 1q23-25, PCAP on chromosome 1q42-43, CAPB on chromosome 1p36, linkage to chromosome 8p22-23, HPC2 on chromosome 17p, HPC20 on chromosome 20q13, and HPCX on chromosome Xq27-28. These linkage findings lead to refined mapping and mutation screening of several strong candidate genes, including ELAC2, RNASEL and MSR1. Up to now, a total of 10 genome-wide linkage scans for prostate cancer susceptibility have been completed, and are reviewed. Furthermore, recent findings that Gleason's grade, a measure of aggressiveness of prostate cancer, is linked to several genomic regions are reviewed. Finally, the roles of environmental and dietary risk factors, and common genetic polymorphisms of genes likely to play a role in common forms of prostate cancer, are briefly discussed within in the context of searching for genes that influence prostate cancer risk.
Article
Migration of cancer cells is one of the key factors responsible for cancer metastasis. The elucidation of mechanisms responsible for the highly invasive potential of cancer cells can help to identify specific targets for the treatment of cancer patients. Highly invasive cancers are usually characterized by aberrant activity of specific intra- or extracellular molecules such as protein kinases, phosphatases, transcriptional factors, proteolytic enzymes, and others. Protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) are responsible for the constitutive activity of transcriptional factors NF-kappaB and AP-1 in some of the highly invasive cancers. Furthermore, NF-kappaB and AP-1 control the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), and expression of both uPA and uPAR correlates with invasive cancer cell phenotype and poor prognosis. The inhibition of PKC and PI3K signaling (through NF-kappaB and AP-1) suppressed the secretion of uPA, resulting in the inhibition of motility of highly invasive breast cancer cells. Therefore, inhibition of specific target molecules in common signaling pathway(s) responsible for metastatic spread can have potential clinical relevance. This review will summarize different approaches to targeting distinct signaling molecules involved in cancer invasion and metastasis.
Article
Green tea infusion has been shown to inhibit metastatic spreading of the transgenic adenocarcinoma of mouse prostate (TRAMP). Investigation on the molecular mechanisms triggered by the main green tea flavonoid, (-)epigallocatechin-3-gallate (EGCG), shows that EGCG restrains TRAMP-C1 cell proliferation in a dose-dependent manner, at concentrations (IC(50) < 0.2 microM) equivalent to those measured in the plasma of moderate green-tea drinkers. Up to 10 microM, EGCG does not modify the cell-surface immuno-localization of MMP-2, one of the invasion-instrumental proteinases; but while in default culture conditions these cells secrete mainly pro-MMP-2, in the presence of reconstituted basement membrane (Matrigel) they release almost exclusively pro-MMP-9. In contrast, when stimulated to traverse Matrigel toward a chemo-attractant, in addition to pro-MMP-9, they secrete pro-MMP-2. In the presence of 0.2 microM EGCG, only the level of the latter is markedly lowered in the conditioned medium, in parallel with the invasive behavior (>50%). In vivo, s.c. injection of TRAMP-C1 cells dispersed in Matrigel gives origin to a tumor mass, whose growth is not inhibited by green-tea regimen. This growth is contained greater than two-thirds by LPS-triggered polymorpho-nuclear phagocyte (PMN) recruitment but this effect is abolished by green tea. Nevertheless, while tumor-released pro-MMP-2 is activated by co-incubation of TRAMP-C1 cells with PMNs, in the presence of 10 microM EGCG the activation is almost abolished. These results suggest that inflammatory involvement of prostate carcinoma could be efficaciously prevented by green tea with a concomitant lowering of the invasive potential.
Article
In Asia, a variety of dietary products have been used for centuries as popular remedies to prevent or treat different diseases. A large number of herbs and extracts from medicinal mushrooms are used for the treatment of diseases. Mushrooms such as Ganoderma lucidum (Reishi), Lentinus edodes (Shiitake), Grifola frondosa (Maitake), Hericium erinaceum (Yamabushitake), and Inonotus obliquus (Chaga) have been collected and consumed in China, Korea, and Japan for centuries. Until recently, these mushrooms were largely unknown in the West and were considered 'fungi' without any nutritional value. However, most mushrooms are rich in vitamins, fiber, and amino acids and low in fat, cholesterol, and calories. These mushrooms contain a large variety of biologically active polysaccharides with immunostimulatory properties, which contribute to their anticancer effects. Furthermore, other bioactive substances, including triterpenes, proteins, lipids, cerebrosides, and phenols, have been identified and characterized in medicinal mushrooms. This review summarizes the biological effects of Ganoderma lucidum upon specific signaling molecules and pathways, which are responsible for its therapeutic effects.
Article
The objective of this project was to identify some possible mechanisms by which two common phytochemicals, resveratrol and β-sitosterol, inhibit the growth of human prostate cancer PC-3 cells. These mechanisms include the effect of the phytochemicals on apoptosis, cell cycle progression, prostaglandin synthesis and the production of reactive oxygen species (ROS). Prostaglandins have been known to play a role in regulating cell growth and apoptosis. PC-3 cells were supplemented with 50 μM resveratrol or 16 μM β-sitosterol alone or in combination for up to 5 days. Phytochemical supplementation resulted in inhibition in cell growth. β-Sitosterol was more potent than resveratrol and the combination of the two resulted in greater inhibition than supplementation with either alone. Long-term supplementation with resveratrol or β-sitosterol elevated basal prostaglandin release but β-sitosterol was much more potent than resveratrol in this regard. β-Sitosterol was more effective than resveratrol in inducing apoptosis and the combination had an intermediate effect after 1 day of supplementation. Cells supplemented with resveratrol were arrested at the G1 phase and at the G2/M phase in the case of β-sitosterol while the combination resulted in cell arrest at the two phases of the cell cycle. β-Sitosterol increased ROS production while resveratrol decreased ROS production. The combination of the two phytochemicals resulted in an intermediate level of ROS. The observed changes in prostaglandin levels and ROS production by these two phytochemicals may suggest their mediation in the growth inhibition. The reduction in ROS level and increase by resveratrol supplementation in PC-3 cells reflects the antioxidant properties of resveratrol. It was concluded that these phytochemicals may induce the inhibition of tumor growth by stimulating apoptosis and arresting cells at different locations in the cell cycle and the mechanism may involve alterations in ROS and prostaglandin production.
Article
The evolution of taxanes as treatment for androgen-independent prostate cancer hes emerged from both the laboratory and clinic. Docetaxel is a potent in vitro inhibitor of Bcl-2, an antiapoptotic gene. Phase I and II studies with docetaxel alone or in combination with estramustine demonstrated promissing median survivals of 14--23 months, higher than what would have been expected for historic controls. Two randomized trials have proven the superiority of docetaxel based treatment in improving survival in men with androgen-independent prostate cancer. SWOG 99-16 and TAX 327 found that docetaxel-based therapy reduced the risk of death by 20--24% when compared to mitoxantrone-based therapy. Future trials will build on docetaxel-based combinations with novel targeted agents.
Article
Caveolae are 50- to 100-nm omega-shaped invaginations of the plasma membrane that function as regulators of signal transduction. Caveolins are a class of oligomeric structural proteins that are both necessary and sufficient for caveolae formation. Interestingly, caveolin-1 has been implicated in the pathogenesis of oncogenic cell transformation, tumorigenesis, and metastasis. Here, we review the available experimental evidence (gleaned from cultured cells, animal models, and human tumor samples) that caveolin-1 (Cav-1) functions as a "tumor and/or metastasis modifier gene." Genetic evidence from the study of Cav-1(-/-) null mice and human breast cancer mutations [CAV-1 (P132L)] supports the idea that caveolin-1 normally functions as a negative regulator of cell transformation and mammary tumorigenesis. In contrast, caveolin-1 may function as a tumor promoter in prostate cancers. We discuss possible molecular mechanisms to explain these intriguing, seemingly opposing, findings. More specifically, caveolin-1 phosphorylation (at Tyr14 and Ser80) and mutations (P132L) may override or inactivate the growth inhibitory activity of the caveolin-scaffolding domain (residues 82-101).
Article
The effectiveness of androgen ablation in the management of advanced prostate cancer is of limited duration, with the median length of response being only 18-24 months. The transition of the prostate cancer cell to an androgen independent phenotype is a complex process that involves selection and outgrowth of pre-existing clones of androgen-independent cells (clonal selection) as well as adaptive up-regulation of genes that help the cancer cells survive and grow after androgen ablation (adaptation). These two mechanisms share an important pre-requisite characteristic: prostate cancers are heterogeneous tumours comprised of various subpopulations of cells that respond differently to androgen withdrawal therapy. This tumour heterogeneity may reflect either a multifocal origin, adaptation to environmental stimuli, and/or genetic instability of the initial cancer. This review will reexamine the different mechanisms that enable prostate cancer cells to proliferate in an androgen depleted environment.
Article
Ganoderma lucidum (G. lucidum) is a popular medicinal mushroom that has been used as a home remedy for the general promotion of health and longevity in East Asia. The dried powder of G. lucidum, which was recommended as a cancer chemotherapy agent in traditional Chinese medicine, is currently popularly used worldwide in the form of dietary supplements. We have previously demonstrated that G. lucidum induces apoptosis, inhibits cell proliferation, and suppresses cell migration of highly invasive human prostate cancer cells PC-3. However, the molecular mechanism(s) responsible for the inhibitory effects of G. lucidum on the prostate cancer cells has not been fully elucidated. In the present study, we examined the effect of G. lucidum on angiogenesis related to prostate cancer. We found that G. lucidum inhibits the early event in angiogenesis, capillary morphogenesis of the human aortic endothelial cells. These effects are caused by the inhibition of constitutively active AP-1 in prostate cancer cells, resulting in the down-regulation of secretion of VEGF and TGF-beta1 from PC-3 cells. Thus, G. lucidum modulates the phosphorylation of Erk1/2 and Akt kinases in PC-3 cells, which in turn inhibits the activity of AP-1. In summary, our results suggest that G. lucidum inhibits prostate cancer-dependent angiogenesis by modulating MAPK and Akt signaling and could have potential therapeutic use for the treatment of prostate cancer.
Article
Hormone refractory prostate cancer remains a challenge. While only palliative treatment strategies were available for the past several decades, many promising agents have been investigated over the past decade. Of those the taxanes appeared with significant anti-tumor activity and recently, two large randomized controlled trials demonstrated for the first time, a survival and palliative benefit with docetaxel based chemotherapy. In the current era, recurrent disease after local treatment for localized disease is diagnosed long before evidence of systemic disease. With earlier institution of hormonal treatments, patients are becoming "hormone refractory" earlier in the course of their disease with considerable long life expectancy. Hence, there is a greater need than ever for more treatment options for this expanding group of patients. A number of new systemic therapies have recently emerged, based on a deeper understanding of prostate cancer biology. Novel chemotherapeutics such as the epothilones, molecularly targeted therapies against angiogenesis, the proteosome and endothelin receptor antagonists, as well as biological agents such as anti-sense oligonucleotides are being tested as part of the armamentarium. Key to progress in the therapy of this fatal disease is the commitment and timely enrolment of prostate cancer patients in clinical trials.