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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor (EGF) plays a role in the development of prostate cancer, which becomes essential after androgen resistance has emerged. The EGF receptor (EGFR) is therefore a potential target for anticancer therapy. We evaluated the effects of ZD1839 ('Iressa'), an orally active EGFR-tyrosine kinase inhibitor, on prostate cancer cell lines. The effects of ZD1839 were evaluated on the anchorage dependent and independent growth of androgen-responsive (LNCaP) and androgen-independent (DU145 and PC3) cells by a cell proliferation assay, cell counting, and soft agar analysis. Flow cytometric analysis and Western blotting were used to assess the effects on the cell-cycle and on protein expression levels, respectively. ZD1839 caused a dose- and time-dependent growth inhibition in all three cell lines. A dose-dependent supra-additive increase in growth inhibition was observed when ZD1839 was combined with the antiandrogen flutamide or ionizing radiation (IR). The antiproliferative effect of ZD1839 was mainly cytostatic and associated with a block in the G(0)/G(1) phase of the cell-cycle, evident after about 12 h of treatment. In the DU145 cells this block was associated with an increase in expression of the CDK inhibitor p27(Kip1), both in the cytoplasmic and nuclear fractions. The increase in p27(Kip1) was not evident in the LNCaP and PC3 cells. No changes were observed in the expression of cyclin D1 protein. These results demonstrate the antiproliferative effects of ZD1839 on the growth of prostate cancer cells and suggest that inhibition of EGFR-associated signal transduction pathway might represent a promising novel therapeutic strategy for the treatment of prostate cancer.
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PMID:Targeted inhibition of the epidermal growth factor receptor-tyrosine kinase by ZD1839 ('Iressa') induces cell-cycle arrest and inhibits proliferation in prostate cancer cells. 1528 Oct 92

Prostate cancer is the second leading cause of cancer-related deaths in males in the United States. This warrants the development of novel mechanism-based strategies for the prevention and/or treatment of prostate cancer. Several studies have shown that plant-derived alkaloids possess remarkable anticancer effects. Sanguinarine, an alkaloid derived from the bloodroot plant Sanguinaria canadensis, has been shown to possess antimicrobial, anti-inflammatory, and antioxidant properties. Previously, we have shown that sanguinarine possesses strong antiproliferative and proapoptotic properties against human epidermoid carcinoma A431 cells and immortalized human HaCaT keratinocytes. Here, employing androgen-responsive human prostate carcinoma LNCaP cells and androgen-unresponsive human prostate carcinoma DU145 cells, we studied the antiproliferative properties of sanguinarine against prostate cancer. Sanguinarine (0.1-2 micromol/L) treatment of LNCaP and DU145 cells for 24 hours resulted in dose-dependent (1) inhibition of cell growth [as evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], (2) arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis), and (3) induction of apoptosis (as evaluated by DNA ladder formation and flow cytometry). To define the mechanism of antiproliferative effects of sanguinarine against prostate cancer, we studied the effect of sanguinarine on critical molecular events known to regulate the cell cycle and the apoptotic machinery. Immunoblot analysis showed that sanguinarine treatment of both LNCaP and DU145 cells resulted in significant (1) induction of cyclin kinase inhibitors p21/WAF1 and p27/KIP1; (2) down-regulation of cyclin E, D1, and D2; and (3) down-regulation of cyclin-dependent kinase 2, 4, and 6. A highlight of this study was the fact that sanguinarine induced growth inhibitory and antiproliferative effects in human prostate carcinoma cells irrespective of their androgen status. To our knowledge, this is the first study showing the involvement of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery during cell cycle arrest and apoptosis of prostate cancer cells by sanguinarine. These results suggest that sanguinarine may be developed as an agent for the management of prostate cancer.
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PMID:Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery. 1529 76

The development of chemopreventive agents against prostate cancer would benefit from conclusive evidence of their efficacy in animal models that emulate human disease. To date there has been little in vivo evidence supporting their preventive capabilities. The 12T-10 Lady transgenic model spontaneously develops localized prostatic adenocarcinoma and neuroendocrine cancer followed by metastases, recapitulating the natural history of human prostate cancer in many respects. Using male Lady version of the transgenic adenocarcinoma of the mouse prostate mice, we show that administration of antioxidants (vitamin E, selenium, and lycopene) in the diet dramatically inhibits prostate cancer development and increases the disease free survival. Treatment of animals with the antioxidants resulted in a 4-fold reduction in the incidence of prostate cancer compared with the untreated animals. Prostate cancer developed in 73.68% (14 of 19) and 100% (19 of 19) of the animals from the standard and high fat diet, respectively. In contrast, only 10.53% (2 of 19) and 15.79% (3 of 19; P < 0.0001) of the animals in the standard and high fat diets supplemented with antioxidants developed tumors. The micronutrients were well tolerated with no evidence of antioxidant-related toxicity. Histopathological analysis confirmed absence of cancer in the additive treated groups. Immunohistochemistry demonstrated a strong correlation between disease-free state and increased levels of the prognostic marker p27(Kip1) and a marked decrease in proliferating cell nuclear antigen expression. These observations provide support for the chemopreventive effect of these micronutrients and some clues as to their mechanism of action.
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PMID:Antioxidants block prostate cancer in lady transgenic mice. 1531 34

Early diagnosis of prostate cancer holds tremendous promise for the effective therapy and impact on survival of prostate cancer patients. High-grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted as a lesion indicative of a late pathological event in the premalignant changes leading to full development of prostate cancer. This review seeks to identify specific molecular events that may be linked directly to the molecular transition from benign prostate epithelial cells to prostate carcinoma. HGPIN is pathologically detected in a limited group of men undergoing prostate cancer screening for an elevated serum prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE). Loss of apoptotic control provides a molecular basis for the contribution of specific defective steps in the pathway towards development and progression of prostate cancer. Comparative dissection of the apoptosis status and expression profile of key apoptotic regulators among foci of highly proliferative benign prostatic epithelium, PIN and prostate adenocarcinoma from adjacent areas of the same gland revealed a novel insight into the dysfunctional apoptosis events contributing to prostate carcinogenesis. The sequential and notable loss of the three critical signaling components of the apoptotic action of transforming growth factor-beta (TGF-beta), in the prostate, that is, the transmembrane receptor II (TbetaRII), the key cell cycle inhibitor p27(Kip1), as well as the protagonist downstream effector of the TGF-beta signaling mechanism, Smad4, points to their potential value to 'faithfully' characterize HGPIN, as a premalignant prostate lesion. Recent evidence on the molecular changes in apoptosis regulators contributing to HGPIN and their role as molecular markers of disease onset, as well as candidates for therapeutic targeting/chemoprevention of prostate cancer in its early stages will be discussed.
Prostate Cancer Prostatic Dis 2005
PMID:Apoptotic regulators in prostatic intraepithelial neoplasia (PIN): value in prostate cancer detection and prevention. 1547 76

Liver X receptors function as central transcriptional regulators for lipid homeostasis, for which agonists have been developed as potential drugs for treatment of cardiovascular diseases and metabolic syndromes. Because dysregulation of lipid metabolism has been implicated in sex hormone-dependent cancers, we investigated the effect of liver X receptor agonists on prostate and breast cancer cell proliferation. Treatment of human prostate cancer LNCaP cell lines with the synthetic liver X receptor agonist T0901317 decreased the percentage of S-phase cells in a dose-dependent manner and increased the expression of cyclin-dependent kinase inhibitor p27(Kip-1) (p27). Knockdown of p27 by RNA interference blocks T0901317-induced growth inhibition, suggesting that p27 expression plays a crucial role in this signaling. Liver X receptor agonists also inhibited the proliferation of other prostate and breast cancer cell lines. The level of liver X receptor alpha expression correlated directly with sensitivity to growth inhibition by liver X receptor agonists. Retroviral expression of liver X receptor alpha in human breast cancer MDA-MB435S cells, which express low levels of endogenous liver X receptors and are insensitive to T0901317, sensitized these cells to T0901317. Consistent with our observations in LNCaP cells, T0901317 induces dramatic up-regulation of p27 in liver X receptor alpha-overexpressing MDA-MB435S cells. Furthermore, oral administration of T0901317 inhibited the growth of LNCaP tumors in athymic nude mice. Based on these results, modulation of the liver X receptor signaling pathway is a new target for controlling tumor cell proliferation; therefore, liver X receptor agonists may have utility as antitumorigenic agents.
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PMID:Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. 1552 Jan 70

The PTEN tumor suppressor gene is a frequent target of somatic mutation, particularly in glioblastoma multiform and prostate cancer. The expression of PTEN in PTEN-mutant glioblastoma cells leads to a cell cycle arrest in G(0)/G(1) that is mediated at least partially by increased p27(kip1) levels. Here we show that p27(kip1) is not regulated by transcriptional control but that p27(kip1) protein shows increased stability after inhibition of the phosphoinositide (PI) 3-kinase pathway. Because p27(kip1) protein stability is known to be regulated by phosphorylation, we have examined modifications in the phosphorylation pattern after PI 3-kinase inhibition. Biochemical evidence suggests that p27(kip1) is phosphorylated on several serine residues, including Ser-10 and Ser-178, but that phosphorylation is unaltered by PI 3-kinase activity. This is further confirmed by the inducible expression of p27(kip1) phosphorylation site mutants, suggesting that p27(kip1) is destabilized in a phosphorylation-independent manner by the PI 3-kinase pathway at the G(1)/S transition.
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PMID:Phosphorylation-independent stabilization of p27kip1 by the phosphoinositide 3-kinase pathway in glioblastoma cells. 1554 3

Lack of life-prolonging therapies has provided much of the impetus for seeking complementary and alternative management/treatment options by prostate cancer (CaP) patients. Among these, the use of dietary supplements and botanical products has been showing a sustained increase in recent years, owing in part to some encouraging pre-clinical and clinical data shown in a limited number of herbal products. Notably, however, the majority of herbal and dietary supplement products have not been rigorously studied with regard to their efficacy. In vitro mechanistic experiments are considered essential preludes and requisites to more lengthy and costly animal and human studies, in that they may provide relevant insights and scientific basis for effects some of these products purportedly might demonstrate. In vitro studies in our laboratory have shown that a polyherbal supplement, Equiguard, exhibits anti-tumor activity against hormone dependent LNCaP cells cultured in both androgen-proficient (FBS) and -deficient (CS-FBS) conditions. Clinically relevant anti-prostate cancer effects of Equiguard are vividly illustrated by growth suppression and down regulated expression of prostate specific genes, respectively, androgen receptor (AR) and prostate specific antigen (PSA). However, the mechanistic bases contributing to these effects have not been well characterized. This communication describes experiments aimed at further understanding growth arrest elicited by Equiguard in LNCaP cells cultured in FBS and CS-FBS conditions. We have focused on aspects of cell cycle control and induction of apoptosis. Regulation of cell cycle progression by Equiguard was analyzed by examining changes in the expression of Rb and cyclins D/E. Using Western blot analysis, we showed that treatment caused inhibition of Rb phosphorylation, which was accompanied by the reduction of cyclins D/E expression, in both culture conditions. Moreover, cells treated with Equiguard and cultured with FBS-supplemented media showed up-regulation of cyclin-dependent kinase inhibitor Kip1/p27. These results support the interpretation that suppression of Rb phosphorylation mediated the observed growth arrest induced by Equiguard under androgen-proficient condition. In contrast, Equiguard-treated cells cultured in CS-FBS had lowered expression of the Kip1/p27, suggesting that different control mechanisms, possibly evoked by changes in cellular microenvironments, contributed to growth suppression by Equiguard. The growth suppressive effects of Equiguard in both culture conditions were also evaluated with respect to induction of apoptosis. While Equiguard elicited apoptosis was accompanied by an increase in the level of cytosolic cytochrome c, the relative accumulation of cytochrome c in the cytosol was unaffected by culture conditions. These results suggest that the ability to trigger apoptosis as one aspect of the control of cell growth by Equiguard is integrally linked to the release of cytochrome c, by a mechanism largely independent of the presence of androgens.
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PMID:Equiguard suppresses androgen-dependent LNCaP prostate cancer cell proliferation by targeting cell cycle control via down regulation of the retinoblastoma protein Rb and induction of apoptosis via the release of cytochrome c. 1554 20

Prostate cancer (PCA) is the most common invasive malignancy and the second leading cause of cancer-related deaths in the US male population. One approach to control this malignancy is its preventive intervention by dietary agents. Inositol hexaphosphate (IP6), a dietary constituent, has shown promising efficacy against various cancers; however, limited studies have been performed with IP6 against PCA. Here, we investigated the growth-inhibitory effect and associated mechanisms of IP6 in androgen-dependent human prostate carcinoma LNCaP cells. IP6 treatment of cells resulted in a strong growth inhibition and an increase in G1 cell population. In mechanistic studies, IP6 resulted in an increase in cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27 levels, together with a decrease in cyclin-dependent kinase (CDK) 4 and cyclin D1 protein levels. An increase in CDKI levels by IP6 also led to a concomitant increase in their interactions with CDK2 and CDK4, together with a strong decrease in the kinase activity of both CDKs. Downstream in CDKI-CDK-cyclin cascade, consistent with its inhibitory effect on CDK kinase activity, IP6 treatment of cells increased hypophosphorylated levels of retinoblastoma (Rb) with a decrease in Rb phosphorylation at serine 780, 807, and 811 sites, and caused a moderate to strong decrease in the levels of transcription factors E2F1, E2F4, and E2F5. In other studies, IP6 caused a dose- and a time-dependent apoptotic death of LNCaP cells, and a decrease in Bcl2 levels, causing a strong increase in Bax versus Bcl2 ratio, as well as an inhibition of constitutively active AKT phosphorylation. Taken together, these molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest, and apoptotic death of human prostate carcinoma LNCaP cells. Because early clinical PCA growth is an androgen-dependent response, the results of the present study employing androgen-dependent LNCaP cells suggest that IP6 has promise and potential to be effective against PCA.
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PMID:Inositol hexaphosphate inhibits growth and induces G1 arrest and apoptotic death of androgen-dependent human prostate carcinoma LNCaP cells. 1554 74

In human prostate cancer, the frequent down-regulation of p27(kip1) protein expression is correlated with poor clinical outcome, yet p27(kip1) rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating p27(kip1) function for prostate carcinogenesis in the context of a mouse modeling lacking the Nkx3.1 homeobox gene and the Pten tumor suppressor. Unexpectedly, we find that triple mutant mice heterozygous for a p27(kip1) null allele (Nkx3.1(+/- or -/-); Pten(+/-); p27(+/-)) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for p27(kip1) (Nkx3.1(+/- or -/-); Pten(+/-); p27(-/-)) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound p27(kip1) heterozygotes, but is down-regulated in the compound p27(kip1) homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct p27(kip1) gene doses, we show that prostate tumorigenicity depends on levels of p27(kip1) and that the consequences of p27(kip1) gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that p27(kip1) possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression.
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PMID:A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis. 1556 26

Epidermal growth factor receptor (EGFR) and HER-2 are associated with a poor prognosis in various cancers, including prostate cancer. Inhibition of these receptors may provide a treatment for hormone-refractory prostate cancer. The presence of HER-2 (Western blot) and EGFR (5830 fmol/mg protein, ligand-binding assay) was assessed in the hormone-refractory human prostate cancer cell line, DU-145. Cells were exposed to the selective EGFR-TKI (EGFR tyrosine kinase inhibitor) gefitinib ('Iressa; ZD1839) and/or the HER-2-targeted monoclonal antibody trastuzumab ('Herceptin'), for 96 h. Irradiation (RX) at 6 Gy the dose causing 50% growth inhibition, was applied 48 h after the start of drug treatment. There was a dose-related effect on cell survival for both ZD1839 and trastuzumab treatments. Combining ZD1839 and trastuzumab led to less than additive effects on cell survival. Chou and Talalay representations further characterised this less than additive effect on cell survival. The application of ZD1839 led to a marked elevation in the level of the negative regulator of cell division, p27. The ZD1839-trastuzumab combination had less of an impact on p27 expression compared with the effect of ZD1839 treatment alone. The lowest expression of the apoptotic-related protein, Bax, was observed in the presence of the drug combination. There was a significant interaction (synergism) between RX and either ZD1839 or trastuzumab treatments. In contrast, the drug combination with RX resulted in antagonistic cytotoxic effects. These results indicate an antagonistic interaction between EGFR and HER-2 targeting and provide molecular mechanisms supporting this observation. Data from DU-145 cells suggest that dual targeting of EGFR and HER-2 may be inappropriate for the treatment of hormone-refractory prostate cancer, especially in the context of their combination with RX.
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PMID:Dual HER 1-2 targeting of hormone-refractory prostate cancer by ZD1839 and trastuzumab. 1557 68


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