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

Although the avocado is known as a rich source of monounsaturated fatty acids, there has been far less attention given to its content of other bioactive substances including carotenoids, which might contribute to cancer preventive properties similar to those attributed to other fruits and vegetables. The yellow-green color of the avocado prompted us to study the carotenoid content of this fruit using established methods in our laboratory. The California Hass avocado (Persea americana Mill.) was selected for study, because it is the most commonly consumed variety in the southwest United States. These avocados were found to contain the highest content of lutein among commonly eaten fruits as well as measurable amounts of related carotenoids (zeaxanthin, alpha-carotene, and beta-carotene). Lutein accounted for 70% of the measured carotenoids, and the avocado also contained significant quantities of vitamin E. An acetone extract of avocado containing these carotenoids and tocopherols was shown to inhibit the growth of both androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines in vitro. Incubation of PC-3 cells with the avocado extract led to G(2)/M cell cycle arrest accompanied by an increase in p27 protein expression. Lutein alone did not reproduce the effects of the avocado extract on cancer cell proliferation. In common with other colorful fruits and vegetables, the avocado contains numerous bioactive carotenoids. Because the avocado also contains a significant amount of monounsaturated fat, these bioactive carotenoids are likely to be absorbed into the bloodstream, where in combination with other diet-derived phytochemicals they may contribute to the significant cancer risk reduction associated with a diet of fruits and vegetables.
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PMID:Inhibition of prostate cancer cell growth by an avocado extract: role of lipid-soluble bioactive substances. 1562 37

New drugs and new combinations of drugs have recently shown promising clinical activity in hormone refractory prostate cancer. We studied the association of gefitinib with trastuzumab on the androgen-refractory prostate cancer cell line DU145 expressing both epidermal growth factor receptor (EGFR) and HER-2. Drug combinations with radiotherapy (RT) were considered along with the analysis of factors linked to cell proliferation and apoptosis. The antitumour effects of gefitinib were more pronounced than those observed with trastuzumab. In mice receiving the gefitinib-trastuzumab combination, reduction in tumour volume was inferior to that predicted by the observed impact of the agents alone. The presence of trastuzumab markedly attenuated the relative increase on p27 expression and the Bax:Bcl2 ratio induced by gefitinib. The combination gefitinib-RT had similar antitumour effects as those predicted by the impact of the individual treatments, whereas the effect of the trastuzumab-RT combination was inferior to that predicted by the individual effects. The present data should be borne in mind when designing new clinical schedules for treatment of hormone-refractory prostate cancer including the use of HER inhibitors.
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PMID:Gefitinib-trastuzumab combination on hormone-refractory prostate cancer xenograft. 1591

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

The immunohistochemical expressions (IE) of p27(kip1) and Ki-67 (MIB-1), both involved in cell cycle regulation and cell proliferation, and their ability to predict biochemical failure, were assessed in patients with clinically localized prostate cancer who had underdone radical prostatectomy of curative intent. In addition, p27(kip1) and Ki-67 (MIB1) expressions were correlated with several pre-operative and post-operative parameters, such as Gleason score, extracapsular extension, seminal vesicle involvement, pelvic lymph nodes metastasis, positive surgical margins, coexistence of high-grade prostatic intraepithelial neoplasia, tumour size, prostate volume and PSA levels. Our analysis involved 130 consecutive radical prostatectomy specimens. A statistically significant correlation of low p27(kiP1) IE with seminal vesicles involvement, increased tumour volume and high pre-operative PSA values was documented. Low p27(kiP1) IE was significantly correlated with an increased likelihood of biochemical failure after radical prostatectomy. In addition, the increased IE of Ki-67 (MIB1) correlated significantly with metastatic disease in the pelvic lymph nodes and was a significant predictor of biochemical failure. Cox regression analysis, which included p27(kip1) expression, Ki-67 (MIB1) expression and all the pre-operative and post-operative parameters, showed that pelvic lymph node involvement and Ki-67 (MIB1) IE were independent prognostic markers of biochemical failure after radical prostatectomy.
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PMID:p27(kip1) and Ki-67 (MIB1) immunohistochemical expression in radical prostatectomy specimens of patients with clinically localized prostate cancer. 1609 46

We have demonstrated that phenylacetate (PA)induced cell cycle arrest in human prostate cancer is mediated by increase of p27. In this study, we further investigated the mechanism of PA-induced p27 expression in prostate cancer cells (LNCaP, androgen-independent LNCaP [AIDL] and PC-3). A striking decrease in Skp2 mRNA and protein expression and reciprocal increase in p27 protein level were observed in three PA-treated prostate cancer cells. Interestingly, reduction of phospho-Akt and up-regulation of p27 mRNA levels were observed only in PC-3 cells. No significant differences were found in phospho-Akt and p27 mRNA levels in LNCaP and AIDL. In vitro ubiquitination assay showed a decreased p27 ubquitination in PA-treated prostate cancer cells. Our results suggest that PA attenuated Skp2 expression, thereby inhibiting ubiquitination and promoting p27 accumulation in all three prostate cancer cell lines. Therapeutic strategies designed to reduce Skp2 may clinically play an important role in the treatment of both androgen-sensitive and hormone-refractory prostate cancer.
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PMID:Down-regulation of Skp2 is correlated with p27-associated cell cycle arrest induced by phenylacetate in human prostate cancer cells. 1615 21

Prostate cancer is the most common invasive malignancy and the second leading cause of cancer-related deaths among U.S. males, with a similar trend in many Western countries. One approach to control this malignancy is its prevention through the use of agents present in diet consumed by humans. Pomegranate from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. We recently showed that pomegranate fruit extract (PFE) possesses remarkable antitumor-promoting effects in mouse skin. In this study, employing human prostate cancer cells, we evaluated the antiproliferative and proapoptotic properties of PFE. PFE (10-100 microg/ml; 48 h) treatment of highly aggressive human prostate cancer PC3 cells resulted in a dose-dependent inhibition of cell growth/cell viability and induction of apoptosis. Immunoblot analysis revealed that PFE treatment of PC3 cells resulted in (i) induction of Bax and Bak (proapoptotic); (ii) down-regulation of Bcl-X(L) and Bcl-2 (antiapoptotic); (iii) induction of WAF1/p21 and KIP1/p27; (iv) a decrease in cyclins D1, D2, and E; and (v) a decrease in cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. These data establish the involvement of the cyclin kinase inhibitor-cyclin-cdk network during the antiproliferative effects of PFE. Oral administration of PFE (0.1% and 0.2%, wt/vol) to athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels. We suggest that pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer in humans.
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PMID:Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. 1619 56

Here, we assessed and compared the anticancer efficacy and associated mechanisms of silymarin and silibinin in human prostate cancer (PCA) PC3 cells; silymarin is comprised of silibinin and its other stereoisomers, including isosilybin A, isosilybin B, silydianin, silychristin and isosilychristin. Silymarin and silibinin (50-100 microg/ml) inhibited cell proliferation, induced cell death, and caused G1 and G2-M cell cycle arrest in a dose/time-dependent manner. Molecular studies showed that G1 arrest was associated with a decrease in cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)4, CDK6 and CDK2 protein levels, and CDK2 and CDK4 kinase activity, together with an increase in CDK inhibitors (CDKIs) Kip1/p27 and Cip1/p21. Further, both agents caused cytoplasmic sequestration of cyclin D1 and CDK2, contributing to G1 arrest. The G2-M arrest by silibinin and silymarin was associated with decreased levels of cyclin B1, cyclin A, pCdc2 (Tyr15), Cdc2, and an inhibition of Cdc2 kinase activity. Both agents also decreased the levels of Cdc25B and cell division cycle 25C (Cdc25C) phosphatases with an increased phosphorylation of Cdc25C at Ser216 and its translocation from nucleus to the cytoplasm, which was accompanied by an increased binding with 14-3-3beta. Both agents also increased checkpoint kinase (Chk)2 phosphorylation at Thr68 and Ser19 sites, which is known to phosphorylate Cdc25C at Ser216 site. Chk2-specific small interfering RNA largely attenuated the silymarin and silibinin-induced G2-M arrest. An increase in the phosphorylation of histone 2AX and ataxia telangiectasia mutated was also observed. These findings indicate that silymarin and silibinin modulate G1 phase cyclins-CDKs-CDKIs for G1 arrest, and the Chk2-Cdc25C-Cdc2/cyclin B1 pathway for G2-M arrest, together with an altered subcellular localization of critical cell cycle regulators. Overall, we observed comparable effects for both silymarin and silibinin at equal concentrations by weight, suggesting that silibinin could be a major cell cycle-inhibitory component in silymarin. However, other silibinin stereoisomers present in silymarin also contribute to its efficacy, and could be of interest for future investigation.
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PMID:Silymarin and silibinin cause G1 and G2-M cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of flavanone silibinin with flavanolignan mixture silymarin. 1620 33

A panel of expression markers was validated and used to document that, when radical prostatectomy specimens are cultured in low (i.e., <260 micromol/L)-calcium (Ca2+)-serum-free, growth factor-defined (SFD) medium, what grows out are not prostatic cancer cells but basally derived normal transit-amplifying prostatic epithelial cells. The selective outgrowth of the normal transit-amplifying versus prostatic cancer cells is due to the differential effect of low-Ca2+ medium on the structure of Notch-1 and E-cadherin signaling molecules. In low-Ca2+ medium, Notch-1 receptor is conformationally in a constitutively active, cell autonomous form not requiring reciprocal cell-cell (i.e., ligand) interaction for signaling. Such signaling is required for survival of transit-amplifying cells as shown by the death of transit-amplifying cells induced by treatment with a series of chemically distinct gamma-secretase inhibitors to prevent Notch-1 signaling. Conversely, in low-Ca2+ medium, E-cadherin is conformationally inactive preventing cell-cell homotypic interaction, but low cell density nonaggregated transit-amplifying cells still survived because Notch-1 is able to signal cell autonomously. In contrast, when medium Ca2+ is raised to >400 micromol/L, Notch-1 conformationally is no longer constitutively active but requires cell-cell contact for reciprocal binding of Jagged-1 ligands and Notch-1 receptors between adjacent transit-amplifying cells to activate their survival signaling. Such cell-cell contact is enhanced by the elevated Ca2+ inducing an E-cadherin conformation allowing homotypic interaction between transit-amplifying cells. Such Ca(2+)-dependent, E-cadherin-mediated interaction, however, results in cell aggregation, stratification, and inhibition of proliferation of transit-amplifying cells via contact inhibition-induced up-regulation of p27/kip1 protein. In addition, transit-amplifying cells not contacting other cells undergo squamous differentiation into cornified (i.e., 1% SDS insoluble) envelopes and death in the elevated Ca2+ medium. Stratification and contact inhibition induced by elevated Ca2+ are dependent on E-cadherin-mediated homotypic interaction between transit-amplifying cells as shown by their prevention in the presence of a cell-impermanent, E-cadherin neutralizing antibody. In contrast to growth inhibition of normal transit-amplifying cells, supplementation of low-Ca(2+)-SFD medium with 10% FCS and raising the Ca2+ to >600 micromol/L stimulates the growth of all prostate cancer cell lines tested. Additional results document that, at physiologic levels of Ca2+ (i.e., >600 micromol/L), prostatic cancer cells are not contact inhibited by E-cadherin interactions and Notch-1 signaling is no longer required for survival but instead becomes one of multiple signaling pathways for proliferation of prostatic cancer cells. These characteristic changes are consistent with prostate cancer cells' ability to metastasize to bone, a site of high-Ca2+ levels.
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PMID:Role of notch-1 and E-cadherin in the differential response to calcium in culturing normal versus malignant prostate cells. 1623 Mar 88

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.
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PMID:Prevalent mutations in prostate cancer. 1626 36

Novel approaches for the early detection of urogenital cancers are urgently needed. Metastatic renal cell carcinoma (RCC) has a poor prognosis and unpredictable course and to date there are no molecular markers that reliably protect RCC outcome. A novel kidney cancer marker, carbonic anhydrase IX (CA IX), was investigated as an independent prognostic factor for survival for patients with metastatic RCC. In patients with non-metastatic RCC low CAIX predicted a worse outcome similar to patients with metastatic disease and overall CAIX expression decreased with development of metastasis. CAIX reflects significant changes in tumour biology, which may be used to predict clinical outcome and identify high-risk patients for adjuvant-targeted therapies. With regard to prostate cancer there are a number of putative biomarkers, although there are limited studies providing clinical correlations in humans. Potential biomarkers include caveolin-1, p-Akt, p27, the met oncogene, Ki67 (MIB-1), 8q24 over-expression, polycomb protein EZH2, plasma TGF-B1 and IL-6 among others. The laboratory has concentrated on the Prostate Stem Cell Antigen (PSCA) which is increased in patients with more aggressive features, that is higher Gleason grade and higher stage. Highest expression is seen in metastatic lesions to bone and staining for PSCA may predict for disease progression or recurrence. Also promising is the finding reported by the group that expression of p27 in radical prostatectomy specimens correlates with biochemical recurrence. Loss of p27 (defined as absent expression in more than 70% of the specimen) is an independent predictor of recurrence among all patients and among the sub-set with organ confined and extra-capsular disease. The data also shows that p27 can predict outcome among patients with positive surgical resection margins. As with other biomarkers, major questions still to be addressed is the requirement for universal application with uniform scoring and the need for prospective studies in randomized clinical trials.
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PMID:Biomarker discovery in urogenital cancer. 1629 16


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