Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are many epigenetic variables that affect the biological responses of autocrine, paracrine and endocrine regulatory molecules, which determine the growth and development of different cancers including prostate cancer (PCA). One of the focuses of the current cancer chemoprevention studies is the search for non-toxic chemopreventive agents that inhibit mitogenic and cell survival signaling in cancer cells. In general, advanced stage cancer cells harbor many constitutively active mitogenic signaling and anti-apoptotic mechanisms, which make them less dependent on external growth factors as well as resistant to chemotherapeutic agents. In this regard, silibinin (a naturally occurring flavanone) has shown the pleiotropic anticancer effects in different cancer cells. Our extensive studies with PCA have shown that inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling are the most likely molecular targets of silibinin's efficacy in PCA. We have observed that silibinin inhibits prostate tumor growth in animal models without any apparent signs of toxicity. At the same time, silibinin is also physiologically available in different organs of the body including plasma and prostate, which is generally required for the pharmacological dosing and translational mechanistic studies of the compound. There are substantial amount of data to support the inhibitory effect of silibinin on mitogenic and cell survival signaling in PCA, which are reviewed in the present communication.
 ...
PMID:A cancer chemopreventive agent silibinin, targets mitogenic and survival signaling in prostate cancer. 1547 49

Adipocyte-fatty acid binding protein (A-FABP) is a 14-15 kDa cytoplasmic protein that binds unesterified fatty acids (FA). It is believed that A-FABP is present in normal cells and disappears in cancer cells. Prostate cancer DU145 cells lack expression of A-FABP. Here, we report that transfection of A-FABP blocked growth of DU145 cells suggesting its role as a tumor suppressor. A-FABP transfected- prostate cancer DU145 cells underwent apoptosis when induced to overexpress A-FABP using an ecdysone-controlled expression system. DU145 cell cultures in complete medium exhibited a maximum of approximately 28% of apoptotic cells after 96 h of exposure to an ecdysone analog, Ponasterone A. We found that the possible mechanisms leading to the observed apoptotic effect may be due, in part, to an overexpression of tumor necrosis factor-alpha (TNF-alpha) and a moderate downregulation of transforming growth factor-alpha (TGF-alpha) in DU145 cells overexpressing A-FABP. The epidermal growth factor receptor (EGFR)/phosphatidyl inositol 3-kinase (PI 3-kinase) signaling pathway was not altered in these cells, suggesting that A-FABP may cause apoptosis by inducing downregulation of essential autocrine growth factors and/or upregulation of pro-apoptotic ones.
 ...
PMID:Adipocyte-fatty acid binding protein induces apoptosis in DU145 prostate cancer cells. 1550 4

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.
 ...
PMID:Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. 1552 6

Combination therapy including antisense oligonucleotides (ODNs) with traditional chemotherapeutic agents offers potential benefits by increasing the effectiveness of the chemotherapeutics, reducing their effective dosage, and simultaneously reducing toxicity. Previously we have reported that antisense ODNs specific for transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR) (MR1 and MR2, respectively), are effective against the PC-3 in vitro and in vivo prostate cancer models. In this series we evaluated these antisense ODNs in various combinations and treatment cycles with paclitaxel (Taxol), cyclophosphamide (Cytoxan), mitoxantrone, carboplatin, cisplatin, and oxaliplatin in order to identify synergistic effects.We found that when either of the ODNs were simultaneously administered with Taxol, no synergistic activity was noted. However, when sequentially administered in a series 1 d apart, a pretreatment with the ODN directed against TGF-alpha (6.64 microm) followed by Taxol (5 nm) had significantly (p <0.001) greater activity than these agents similarly administered in the reverse order or simultaneously. When Cytoxan was administered in sequence with both ODNs significantly increased growth inhibition was obtained compared to when Cytoxan was administered alone. A 1 d treatment of PC-3 cells with Cytoxan followed the next day with MR1 was significantly more effective (p <0.0001). The reverse order, a pretreatment with MR1 followed by Cytoxan, also resulted in significant additional inhibition (p=0.0004). Similarly sequenced, MR2 followed by Cytoxan, was also significantly more effective (p=0.0014) than Cytoxan treatment alone. For mitoxantrone, which was administered in combination therapy with ODNs: mitoxantrone with MR1 was significantly more inhibitory than the combination of both MR1 and MR2 ODNs (p=0.006) and also mitoxantrone administered alone (p=0.0012). Mitoxantrone administered with MR1 was not significantly different from mitoxantrone given in combination with MR2. Although mitoxantrone and MR2 was statistically (p=00015) more inhibitory than mitoxantrone alone, this combination was barely more effective (p=0.04) than the MR1 ODN administered alone.
 ...
PMID:Synergistic effects of combination therapy employing antisense oligonucleotides with traditional chemotherapeutics in the PC-3 prostate cancer model. 1557 18

Recent advances in cancer therapy have resulted in the development of drugs that target mechanisms involved in neoplastic change and angiogenesis. One example is gefitinib ('Iressa', ZD1839), an orally-active epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks EGFR signaling in vitro, thereby inhibiting the growth, proliferation and survival of many solid tumors. Clinical trial data show that gefitinib monotherapy is generally well tolerated in patients with a wide range of tumor types (including lung, head and neck, colon, breast, and prostate cancers). The most common adverse events (AEs) were mild and reversible skin and gastrointestinal disorders (National Cancer Institute common toxicity criteria grade 1/2). Few drug-related grade 3/4 skin and gastrointestinal disorders were observed, and drug-related hematologic AEs were uncommon. The clinical benefit of gefitinib in non-small-cell lung cancer (NSCLC), head and neck, colon, breast, and prostate cancer is being investigated, as antitumor activity has been observed in a range of solid tumors, including NSCLC. In two large phase II NSCLC trials (IDEAL ['Iressa' Dose Evaluation in Advanced Lung Cancer] 1 and 2) objective tumor responses of 18.4% and 11.8%, and disease control rates (complete and partial responses plus stable disease) of 54.4% and 42.2%, respectively, were seen in patients given 250 mg/day gefitinib. Additionally, disease-related symptoms improved in 40.3% and 43.1% of patients, and improved quality of life was experienced by 23.9% and 34.3% patients in IDEAL 1 and 2, respectively. Furthermore, the majority of patients who had an objective response also experienced symptom improvement. Gefitinib has been approved for the treatment of advanced NSCLC in Japan, the USA, and other countries. This review discusses the potential of gefitinib in a wide range of solid tumors. 'Iressa' is a trademark of the AstraZeneca group of companies.
 ...
PMID:Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors. 1558 98

De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.
 ...
PMID:Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. 1561 53

Interference with the activation of growth factor receptors, specifically epidermal growth factor receptor (EGFR), represents a promising strategy for the development of novel and selective anticancer therapies. We reported that EGFR-related peptide (ERRP), a recently isolated negative regulator of EGFR, could be a potential therapeutic agent for colorectal cancer. To determine whether ERRP could potentially be a therapeutic agent for prostate carcinoma, we examined the effect of recombinant ERRP on the growth of the prostate cancer cell line PC-3 in vitro. Events of the EGFR signal transduction pathways were also examined. ERRP caused a marked inhibition of cell growth in a dose- and time-dependent manner and also induced apoptosis. The latter was evidenced by increased number of apoptotic cells, activation of caspase-3, and cleavage of poly(ADP-ribose)polymerase. The transforming growth factor-alpha-induced stimulation of cell growth and activation of EGFR was also inhibited by ERRP. These changes were accompanied by a concomitant attenuation of activation of Akt and mitogen-activated protein kinases as well as basal and transforming growth factor-alpha-induced activation of nuclear factor-kappaB. Inhibition of EGFR activation by ERRP could be partly attributed to increased sequestration of EGFR ligands. In summary, our data show that ERRP inhibits the growth of prostate cancer cells by attenuating EGFR signaling processes. ERRP could potentially be an effective therapeutic agent for prostate cancer.
 ...
PMID:Epidermal growth factor receptor-related peptide inhibits growth of PC-3 prostate cancer cells. 1712 43

Prostate cancer is a leading cause of morbidity and mortality among males. Androgen ablation as initial therapy for advanced prostate cancer provides high response rates but does not cure disease, as nearly all men with metastases will eventually progress to hormone-refractory prostate cancer (HRPC). Present chemotherapy regimens for HRPC can provide palliation and have recently demonstrated an increase in overall survival. Over the past 2 decades, these regimens represent clear advances in the treatment of metastatic prostate cancer but also demonstrate that newer therapies are needed. Studies are ongoing to provide viable alternatives among traditional cytotoxic therapies as well as among novel agents targeting specific molecular pathways. This article reviews some of the newer therapies being developed and evaluated, including the epothilone analogues, human epidermal growth factor receptor pathway inhibitors, angiogenesis inhibitors, and endothelin receptor antagonists.
Clin Prostate Cancer 2004 Dec
PMID:Newer therapies in advanced prostate cancer. 1563 81

Cetrorelix, a luteinising hormone-releasing hormone (LHRH) analogue, has been shown to limit growth of the human androgen-independent prostate cell line DU-145, although other inhibitory actions may also be affected. Both growth and invasion of DU-145 cells are linked to autocrine epidermal growth factor receptor (EGFR) signalling. Invasiveness requires not only cells to migrate to conduits, but also reduced adhesiveness between tumour cells to enable separation from the tumour mass. Thus, we investigated whether Cetrorelix alters the DU-145 cell-cell adhesion and if this occurs via altered EGFR signalling. Pharmacologic levels of Cetrorelix limited the invasiveness of a highly invasive DU-145 subline overexpressing full-length EGFR (DU-145 WT). Extended exposure of the cells to Cetrorelix resulted in increased levels of the cell-cell adhesion complex molecules E-cadherin, alpha- and beta-catenin, and p120. Puromycin blocked the increases in E-cadherin and beta-catenin levels, suggesting that de novo protein synthesis is required. The Cetrorelix effect appears to occur via transmodulation of EGFR by a protein kinase C (PKC)-dependent mechanism, as there were no changes in DU-145 cells expressing EGFR engineered to negate the PKC transattenuation site (DU-145 A654); downregulation of EGFR signalling produced a similar upregulation in adhesion complex proteins, further suggesting a role for autocrine signalling. Cetrorelix increased the cell-cell adhesiveness of DU-145 WT cells to an extent similar to that seen when autocrine EGFR signalling is blocked; as expected, DU-145 A654 cell-cell adhesion also was unaffected by Cetrorelix. The increased adhesiveness is expected as the adhesion complex molecules moved to the cells' periphery. These data offer direct insight into the possible crosstalk pathways between the LHRH and EGFR receptor signalling. The ability of Cetrorelix to downregulate EGFR signalling and subsequently reverse the antiadhesiveness found in metastatic prostate cancer highlights a novel potential target for therapeutic strategies.
 ...
PMID:Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline. 1565 36

Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSU-Pr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC50 = 0.1-0.6 microM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC50 = 0.8-2.0 microM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC50 of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC50 of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFR-driven androgen independence.
 ...
PMID:Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro. 3109 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>