Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zinc exhibits inhibitory effects on apoptosis, and a deficiency in this metal generally causes this type of cell death to occur. In the present study, we found that exposure to zinc results in necrosis of prostate carcinoma cells. When zinc acetate was added to LNCaP or PC-3 cells in monolayer culture, they began to detach from the culture dishes, and viability was lost after 4-8 h. Most of the cell death was found to be due to necrosis as determined by double staining with fluorescein-isothiocyanate-labeled annexin V and ethidium bromide, and by detection of hypodiploid cells. Associated with the induction of necrosis was an increase in low molecular-mass proteins, identified by HPLC analysis to be thymosin beta10, parathymosin and GAGE in LNCaP cells, and thymosin beta4, parathymosin and metallothionein in PC-3. The time course of the increase of thymosin beta10 in LNCaP cells and thymosin beta4 in PC-3 cells was consistent with that of appearance of cell detachment and dead cells. These results indicate that zinc can induce necrosis and suggest that production of proteins including beta-thymosins is involved in induction of processes leading to cell detachment.
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PMID:Induction of necrosis by zinc in prostate carcinoma cells and identification of proteins increased in association with this induction. 965 77

Prostatic cancers are well-known to be sensitive to heat stress. However, the mechanism by which the cancer cells are killed by high temperature remains poorly understood. The present study was undertaken to determine the anti-proliferative effects of heat stress on the prostatic cancer cells in culture. Heat shock at 43 degrees C inhibited the cell growth of three different prostatic cell lines. Flow cytometrical analysis using BrdU and PI showed a decrease in the proportion of cells in an S phase, accompanied by cell accumulation in G1 and G2, in both JCA-1 and PC-3 but not in LNcap. Both JCA-1 and PC-3 presented a strong expression of hsp70 at 37 degrees C. The heat shock caused apparent enhancement of the expression of hsp70 through the cell cycle. A treatment at 43 degrees C for 8 hours resulted in not only an apparent increment of positive hsp70 cells, but cells with subdiploid DNA content in LNcap. Flow cytometrical analysis by FITC-labeled Annexin V showed increment of apoptotic cells at 43 degrees C for 8 hours in LNcap cells. The results suggest that apoptosis is an important pathway of heat-induced killing of these cells. In conclusion, the cell growth of prostatic cancers may be affected by the temperature through relationship of the cell cycle and hsp70.
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PMID:[Anti-proliferative effects of heating on the human prostatic carcinoma cells in culture]. 1008 78

Few therapeutic treatment options are available for patients suffering from metastatic androgen-independent prostate cancer. We investigated the ability of the estrogen metabolite 2-methoxyestradiol to inhibit the proliferation of a variety of human prostate cancer cell lines in vitro and to inhibit the growth of androgen-independent prostate cancer in a transgenic mouse model in vivo. Our results showed that 2-methoxyestradiol is a powerful growth inhibitor of LNCaP, DU 145, PC-3, and ALVA-31 prostate cancer cells. Cell flow cytometry of 2-methoxyestradiol-treated DU 145 cells showed a marked accumulation of cells in the G2/M phase of the cell cycle and an increase in the sub-G1 fraction (apoptotic). In addition, staining for annexin V, changes in nuclear morphology, and inhibition of caspase activity support a role for apoptosis. More importantly, we showed that 2-methoxyestradiol inhibits prostate tumor progression in the Ggamma/T-15 transgenic mouse model of androgen-independent prostate cancer without toxic side effects. These results in cell culture and an animal model support investigations into the clinical use of 2-methoxyestradiol in patients with androgen-independent prostate cancer.
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PMID:2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer. 1147 93

Human metallothioneins (MTs) are low-molecular-weight, cysteine-rich, metal ion-binding proteins that constitute the majority of intracellular protein thiols. They are overexpressed in prostate and ovarian cancers and are believed to confer resistance to radiation and cytotoxic anticancer drugs. The aim of this study was to investigate the roles of MTs in prostate and ovarian cancer cells and their possible relationship with other cancer development and progression factors. The main problem in investigating the role of MT, however, is the absence of any known specific inhibitor. To this end, in a previous study, we had developed sequence-specific ribozymes (Rzs) targeting MT and had shown their in cellulo efficacy. Here we show that transient transfection of a vector carrying a hammerhead Rz (Rz4-9), designed to cleave class II MT, in the human prostate cancer cell line PC-3 and the ovarian cancer cell line SKOV-3 resulted in a dose-dependent attenuation of MT-II(a) transcripts and dramatic cell loss. Transient transfection with 2 microg of Rz4-9 vector DNA completely abolished MT-II(a) mRNA levels and induced a 94% and a 67% reduction in cell number in PC-3 cells and SKOV-3 cells, respectively. Fluorescence-activated cell sorting (FACS) showed that the Rz-induced cell loss probably was due to apoptosis, because it was associated with marked increases in the hypodiploid cell population, reaching maximums of 52% and 64% in cultures of PC-3 and SKOV-3, respectively. Additionally, annexin V-propidium iodide double-staining, followed by FACS, confirmed that Rz4-9-induced cell death was due to apoptosis and showed a vector DNA-dependent increase in late apoptotic cell numbers that reached maximums of 80% and 42%, respectively, in PC-3 and SKOV-3 cell cultures transfected with the highest concentration of vector DNA. In parallel experiments, transfection with a vector containing the enzymatically inactive mutant Rz-3-3 or the empty vector was not effective in inducing similar responses. The Rz-induced loss of MT-II(a) mRNA-associated cell death in these cancer cell lines was attended by dose-dependent downregulation of the proto-oncogene c-myc and the apoptosis inhibitory mediator bcl-2, suggesting that these signaling pathways are involved in the process. In conclusion, our data indicate that MT-II(a) is an important cell-survival or anti-apoptotic factor for prostate and ovarian cancer cells and that downregulation of its expression via transgene expression of a sequence-specific Rz is a feasible target for cancer therapy.
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PMID:Ribozyme-mediated downregulation of human metallothionein II(a) induces apoptosis in human prostate and ovarian cancer cell lines. 1180 57

We identified a novel mouse gene, mRTVP-1, as a p53 target gene using differential display PCR and extensive promoter analysis. The mRTVP-1 protein has 255 amino acids and differs from the human RTVP-1 (hRTVP-1) protein by two short in-frame deletions of two and nine amino acids. RTVP-1 mRNA was induced in multiple cancer cell lines by adenovirus-mediated delivery of p53 and by gamma irradiation or doxorubicin both in the presence and in the absence of endogenous p53. Analysis of RTVP-1 expression in nontransformed and transformed cells further supported p53-independent gene regulation. Using luciferase reporter and electrophoretic mobility shift assays we identified a p53 binding site within intron 1 of the mRTVP-1 gene. Overexpression of mRTVP-1 or hRTVP-1 induced apoptosis in multiple cancer cell lines including prostate cancer cell lines 148-1PA, 178-2BMA, PC-3, TSU-Pr1, and LNCaP, a human lung cancer cell line, H1299, and two isogenic human colon cancer cell lines, HCT116 p53(+/+) and HCT116 p53(-/-), as demonstrated by annexin V positivity, phase-contrast microscopy, and in selected cases 4',6'-diamidino-2-phenylindole staining and DNA fragmentation. Deletion of the signal peptide from the N terminus of RTVP-1 reduced its apoptotic activities, suggesting that a secreted and soluble form of RTVP-1 may mediate, in part, its proapoptotic activities.
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PMID:mRTVP-1, a novel p53 target gene with proapoptotic activities. 1197 68

Despite the growing interest in selenium intervention of prostate cancer in humans, scanty information is currently available on the molecular mechanism of selenium action. Our past research indicated that methylseleninic acid (MSA) is an excellent reagent for investigating the anticancer effect of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in PC-3 human prostate cancer cells. After exposure to physiological concentrations of MSA, these cells exhibited a dose- and time-dependent inhibition of growth. MSA retarded cell cycle progression at multiple transition points without changing the proportion of cells in different phases of the cell cycle. Flow cytometric analysis of annexin V- and propidium iodide-labeled cells showed a marked induction of apoptosis by MSA. Array analysis with the Affymetrix human genome U95A chip was then applied to profile the gene expression changes that might mediate the effects of selenium. Gene profiling was done in a time course experiment (at 12, 24, 36, and 48 h) using synchronized cells. A large number of potential selenium-responsive genes with diverse biological functions were identified. These genes fell into 12 clusters of distinct kinetics pattern of modulation by MSA. The expression changes of 10 genes known to be critically involved in cell cycle regulation were selected for verification by Western analysis to determine the reliability of the array data. An agreement rate of 70% was obtained based on these confirmation experiments. The array data enabled us to focus on the role of potential key genes (e.g., GADD153, CHK2, p21(WAF1), cyclin A, CDK1, and DHFR) that might be targets of MSA in impeding cell cycle progression. The data also provide valuable insights into novel biological effects of selenium, such as inhibition of cell invasion, DNA repair, and stimulation of transforming growth factor beta signaling. The present study demonstrates the utility of a genome-wide analysis to elucidate the mechanism of selenium chemoprevention.
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PMID:Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. 1251 77

Screening of synthetic retinoids for activity against prostate carcinoma cell lines has identified antagonists of retinoic acid receptors (RARs) as potent growth inhibitors (Hammond et al, 2001, Br J Cancer 85, 453-462). Here we report that 5 days of exposure to a high-affinity pan-RAR antagonist (AGN194310) abolished growth of prostate carcinoma cells from 14 out of 14 patients, with half-maximal inhibition between 200 and 800 nM. It had similar effects (at approximately 250 nM) on the prostate carcinoma lines LNCaP, DU-145 and PC-3. AGN194310 inhibited the growth of normal prostate epithelium cells less potently, by 50% at approximately 1 microM. The growth of tumour cells was also inhibited more than that of normal cells when RARbeta together with RARgamma, but not RARalpha alone, were antagonised. Treatment of LNCaP cells with AGN194310 arrested them in G1 of cell cycle within 12 h, with an accompanying rise in the level of p21(waf1). The cells underwent apoptosis within 3 days, as indicated by mitochondrial depolarisation, Annexin V binding and DNA fragmentation. Apoptosis was caspase-independent: caspases were neither cleaved nor activated, and DNA fragmentation was unaffected by the pan-caspase inhibitor Z-VAD-FMK. The ability of AGN 194310 to induce apoptosis of prostate cancer cells and its differential effect on malignant and normal prostate epithelial cells suggests that this compound may be useful in the treatment of prostate cancer.
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PMID:An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium. 1526 11

A series of potential DNA-binding antitumor agents, 2-[omega-(alkylamino)alkyl]-9-methoxy-5-nitro-2,6-dihydroindazolo[4,3-bc][1,5]naphthyridines (2a-f), 10-aza derivatives of PZA, has been prepared by condensation of 9-chloro-2-methoxy-6-nitro-5,10-dihydrobenzo[b][1,5]naphthyridin-10-one (6) with the appropriate (omega-aminoalkyl)hydrazine in tetrahydrofuran/methanol. Compound 6 was obtained by heating at 100 degrees C in H(2)SO(4)5, yielded by the condensation of 2,6-dichloro-3-nitrobenzoic acid (4) and 6-methoxy-3-pyridinamine (3). The non-covalent DNA-binding properties of 2 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives against human hormone-refractory prostate adenocarcinoma cell line (PC-3) are described and compared to that of parent drug PZA. We selected the most cytotoxic target derivatives 2c,d, the in vitro inactive 2f, and reference compound PZA to investigate whether in vitro treatment with these drugs was able to induce necrotic and/or apoptotic cell death. To this purpose, we evaluated the percentage of apoptotic cells in PC-3 treated with the target compounds 2c,d,f and reference compound PZA, by Annexin V staining and Propidium iodide (PI)/Annexin V, biparametric flow cytometric analysis and agarose gel electrophoresis.
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PMID:Synthesis and biological evaluation of indazolo[4,3-bc][1,5]naphthyridines (10-aza-pyrazolo[3,4,5-kl]acridines): a new class of antitumor agents. 1549 70

Prostate cancer is the second leading cause of cancer death in the United States and, thus far, there has been no effective therapy for the treatment of hormone-refractory disease. Recently, the androgen receptor (AR) has been shown to play a critical role in the development and progression of the disease. In this report, we showed that knocking down the AR protein level by a small interfering RNA (siRNA) approach resulted in a significant apoptotic cell death as evidenced by an increased annexin V binding, reduced mitochondrial potential, caspase-3/6 activation, and DFF45 and poly(ADP-ribose) polymerase cleavage. The apoptotic response was specifically observed in those siRNA-transfected cells that harbor a native AR gene. No cell death was found in the AR-null prostate cancer cell PC-3 or its subline that has been reconstituted with an exogenous AR gene, as well as two breast cancer cell lines that are AR positive. Moreover, in parallel with the siRNA-induced AR silencing, the antiapoptotic protein Bcl-xL was significantly reduced, which might account for the apoptotic cell death because ectopic enforced expression of Bcl-xL protein partially inhibited apoptosis after AR silencing. Taken together, our data showed that knocking down the AR protein level in prostate cancer cells leads to apoptosis by disrupting the Bcl-xL-mediated survival signal downstream of AR-dependent survival pathway.
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PMID:Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer. 1582 23

This study investigated the anticancer activity and related mechanisms of neolignans, especially threo, erythro-manassantin A (compound 2), which are isolated from Saururus chinensis, in PC-3 cells. Compound 2 strongly inhibited the proliferation of PC-3 cells in a dose-dependent manner. Different cell morphologies were observed depending on the concentration of compound 2, which suggested different growth inhibitory mechanisms. DNA flow cytometry indicated that both low and high concentrations of compound 2 induced the arrest of PC-3 cells in G1 phase. Western blot analyses showed that hyperphosphorylated Rb and E2F-1 were decreased, whereas hypophosphorylated Rb was increased. The cells treated with compound 2 at 200 ng/ml showed shrinkage morphologically, and the staining of annexin V-FITC revealed apoptotic cell death of these cells. The induction of apoptosis was accompanied by the cleavage of caspase-3, -8, and -9, as well as the downregulation of the Bcl-2 and the upregulation of Bax. By contrast, at low compound 2 concentration (1 ng/ml), the cells arrested in G1 showed characteristic changes in morphology, such as an enlarged, flattened cell shape; the majority strongly expressed SA-beta-galactosidase activity. The number of cells undergoing apoptosis was negligible, and no poly(ADP-ribose) polymerase (PARP) cleavage was observed. The increase of p21 was noticed. However, it appeared to be transient rather than sustained. The protein p27 may be important for maintaining the senescence machinery induced by compound 2 because p27 expression was increased at low concentration compared with that at high concentration. In conclusion, compound 2 showed a significant growth inhibitory effect in PC-3 cells via two different mechanisms, i.e., apoptosis at high concentration and senescence at low concentration.
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PMID:Neolignans from Saururus chinensis inhibit PC-3 prostate cancer cell growth via apoptosis and senescence-like mechanisms. 1614 81


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