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)

In this study, we show that LIM kinase 1 (LIMK1), a critical regulator of actin dynamics, plays a regulatory role in tumor cell invasion. We found that the level and activity of endogenous LIMK1 is increased in invasive breast and prostate cancer cell lines in comparison with less invasive cells. Overexpression of LIMK1 in MCF-7 and in MDA-MB-231 human breast cancer cell lines increased their motility, whereas the specific ROCK and Rho inhibitors Y-27632 and C3, respectively, attenuated this effect. In addition, inhibition of LIMK1 activity in the MDA-MB-231 cells by expression of dominant-negative LIMK1 resulted in decreased motility and formation of osteolytic bone lesions in an animal model of tumor invasion. This study shows an important role for LIMK1 signaling in invasion of cancer, demonstrating its potential as a therapeutic molecular target to decrease metastasis.
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PMID:A role for LIM kinase in cancer invasion. 1277 19

In our continuous studies of anticancer activity of steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca (Dioscoreaceae), methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787) were tested for cytotoxicity against human cancer cell lines from leukemia and eight solid tumor diseases. As a result, methyl protoneogracillin was cytotoxic against all the test cell lines with GI(50) < 100 micro M, especially selectively against two leukemia lines (CCRF-CEM and RPMT-8226), one colon cancer line (KM12), two central nervous system (CNS) cancer lines (SF-539 and U251), one melanoma line (M14), one renal cancer line (786-0), one prostate cancer line (DU-145), and one breast cancer line (MDA-MB-435), with GI(50) < or = 2.0 micro M. Leukemia, CNS cancer, and prostate cancer were the most sensitive subpanels, while ovarian cancer was the least sensitive subpanels. The preliminary toxicity studies showed that the maximum tolerant dose was 600 mg/kg for methyl protoneogracillin to mice. Gracillin was cytotoxic against most cell lines with GI(50), TGI and LC(50) at micromolar levels, but no activity against EKVX (non-small cell lung cancer), HT29 (colon cancer), OVCAR-5 (ovarian cancer), and SN12C (renal cancer). Based on structure-activity relationship, C-25 R/S con fi guration was critical for leukemia selectivity between methyl protoneogracillin and methyl protogracillin. F-ring was critical to selectivity between furostanol (methyl protoneogracillin and methyl protogracillin) and spirostanol (gracillin) saponins in this study. By an analysis of COMPARE software, no compounds in the NCI's database had similar mean graphs to those of methyl protoneogracillin and gracillin, respectively, indicating potential novel mechanism(s) of action involved. Put all in together, methyl protoneogracillin has been selected as a potential anticancer candidate for hollow fi ber assay to nude mice, but gracillin will not be pursued due to lack of selectivity against human cancer diseases.
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PMID:The cytotoxicity of methyl protoneogracillin (NSC-698793) and gracillin (NSC-698787), two steroidal saponins from the rhizomes of Dioscorea collettii var. hypoglauca, against human cancer cells in vitro. 1282 Feb 29

Endostatin has been considered a highly specific inhibitor of endothelial cell proliferation and/or migration. To explore the use of endostatin in antiangiogenic gene therapy, we generated a recombinant adenovirus, AdEndo, carrying the gene for mouse endostatin. Injection of 10(9) PFU of AdEndo resulted in a low but significant suppression (25%) of preestablished tumor growth in murine models involving murine Lewis lung carcinoma (LLC) and human breast cancer MDA-MB-231 tumors. Greater anticancer activity was observed when the same dose of AdEndo was injected into two other preestablished murine models involving C51 murine colon cancer and HT29 human colon cancer (55 and 47% tumor growth reduction, respectively). In vitro, endostatin derived from AdEndo-infected MRC-5 fibroblasts inhibited the growth of C51 and HT29 cell lines (72 and 61%, respectively). The extent of this inhibition was comparable to that observed in endothelial cells: 75% for microcapillary endothelial cell line HMEC-1, 52% for human dermal microvascular endothelial cells, 46% for human umbilical vein endothelial cells, and 67% for calf pulmonary arterial endothelial cells. Both endothelial and colon cancer cells showed a clear increase in cell apoptosis (4- to 5-fold for endothelial cells and 5- to 10-fold for colon cancer cells) and an accumulation in the G(1) phase of the cell cycle. This antiproliferative activity was not observed in other tumor cell lines: LLC, MDA-MB-231, murine colon adenocarcinoma MC38, human prostate cancer cell line DU145, and human breast cancer cell line CAL51. Taken together, these results provide evidence that, in addition to its antiangiogenic activity, endostatin exerts a direct anticancer action that appears to be restricted to some tumor cell lines. Thus, endostatin could be used in some colon cancer treatments and its clinical efficacy would depend on the response of tumor cells themselves.
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PMID:Endostatin exhibits a direct antitumor effect in addition to its antiangiogenic activity in colon cancer cells. 1286 17

Prostate cancer is a leading cause of cancer death in American males. Currently, there is no curative therapy available once prostate cancer has metastasized. A major systemic therapy for metastatic prostate cancer is anti-androgen therapy. Unfortunately this therapy is only palliative and rarely curative, and eventually the tumor cells develop resistance to further hormone manipulation. It is therefore imperative to develop alternative effective therapies. In the present study, the effect of a Chinese herbal formula, ZYD88, on regulation of cell growth and cell apoptosis was examined in prostatic tumor cells. ZYD88 decreased cell viability of multiple prostatic tumor cell lines, DU-145, PC-3, MDA-PCa 2b and LNCaP in a time- and dose-dependent manner. It also produced a rapid and dose-dependent increase in caspase 3 activity in LNCaP and PC-3 cells, and induced DNA fragmentation in LNCaP cells, indicating cell apoptosis. In cotransfection assays, ZYD88 inhibited androgen-induced prostate specific antigen (PSA) gene promoter activity, and induced estrogen-target gene promoter activity. These data suggest that ZYD88 is a potential agent for prostate cancer therapy, and deserves further study.
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PMID:The Chinese medicinal herbal formula ZYD88 inhibits cell growth and promotes cell apoptosis in prostatic tumor cells. 1288 51

Breast and prostate cancer are leading causes of cancer death in the Western world. Hormone ablation is the primary therapy for invasive disease, but the tumour often recurs in an androgen or oestrogen receptor negative form for which novel therapies are sought urgently. The vitamin D receptor (VDR) may provide an important alternative therapeutic target. However, cancer cell line models from these tissues display a range of sensitivities to the antiproliferative effects of 1alpha,25dihydroxyvitamin D3 (1alpha,25(OH)2D3). The reason for apparent 1alpha,25(OH)2D3 insensitivity is currently unknown and we have investigated epigenetic mechanisms that may suppress the transcriptional activity of the VDR. Nuclear co-repressors have associated histone deacetylase (HDAC) activity, which keeps chromatin in a closed, transcriptionally silent state. We have found that the aggressive cancer cell lines with relative insensitivity to 1alpha,25(OH)2D3 have elevated nuclear co-repressor levels. For example, PC-3 prostate cancer cells have a significant 1.8-fold elevation in the co-repressor SMRT compared to normal epithelial cells (P < 0.05). We believe that a combination of elevated co-repressor level with reduced VDR content can cause 1alpha,25(OH)2D3 resistance. Consistent with this, we have shown that combining a low dose of HDAC inhibitor Trichostatin A (15 nM TSA) with 1alpha,25(OH)2D3 (100 nM) synergistically inhibits the proliferation of PC-3 prostate and MDA-MB-231 breast cancer cell lines. The inhibition of proliferation was potentiated further by treating cells with 19-nor-hexafluoride vitamin D3 analogues instead of 1alpha,25(OH)2D3, plus TSA. For example, the combination of 1alpha,25(OH)2D3 and TSA-inhibited MDA-MB-231 cell proliferation by 38% (+/-5%), whereas Ro26-2198 (1alpha,25-(OH)2-16,23Z-diene-26,27-F6-19-nor-D3) and TSA inhibited growth by 62% (+/-2%). Therapeutically the hypercalcaemic side effects associated with 1alpha,25(OH)2D3 could be minimized by combining low doses of potent 1a,25(OH)2D3 analogues with HDAC inhibitors as a novel anticancer regime for hormone-insensitive prostate and breast cancer.
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PMID:Antiproliferative signalling by 1,25(OH)2D3 in prostate and breast cancer is suppressed by a mechanism involving histone deacetylation. 1289 15

The third isoform of metallothionein (MT-3) is overexpressed in some breast cancers and its expression is associated with a poor disease outcome. In the PC-3 prostate cancer cell line, MT-3 expression has been shown to inhibit cell growth and increase drug resistance. The goal of the present study was to determine if MT-3 overexpression would influence the growth of human breast cancer cell lines. To determine this, the coding sequence of the MT-3 gene was stably transfected into two estrogen receptor positive (MCF-7 and T-47D) and two estrogen receptor negative cell lines (Hs578T and MDA-MB-231) having no basal expression of MT-3. Cell growth was determined by counting DAPI-stained nuclei, cadmium resistance by the colony formation assay, MT mRNA expression by RT-PCR, and MT protein by immuno-blot. It was demonstrated that MCF-7 and Hs578T cells that overexpress the MT-3 gene were growth inhibited compared to untransfected cells. In contrast, T-47D and MDA-MB-231 cells that overexpress MT-3 were not growth inhibited. Stable transfection of the MT-1E gene had no effect on the growth of any of the four cell lines. It was also demonstrated that the overexpression of both MT-3 and MT-1E only increased the resistance of MCF-7 cells to Cd(+2). In all instances, stable transfection of the MT-3 or MT-1E gene had no effect on the expression of the other MT isoforms. The study shows that MT-3 can influence the growth of some breast cancer cell lines.
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PMID:Stable transfection and overexpression of metallothionein isoform 3 inhibits the growth of MCF-7 and Hs578T cells but not that of T-47D or MDA-MB-231 cells. 1290 21

Bone sialoprotein (BSP) is a major non-collagenous protein found almost exclusively in bone and other mineralized tissues including enamel, dentin and cementum. Although a role for BSP in mineralization has been indicated, BSP also appears to function in patho-physiological processes, including the metastasis of breast and prostate cancer cells to bone. The purpose of this study was to determine the role of BSP in the homing of cancer cells and to provide insights into the role of BSP in physiological as well as pathological processes. We established cultures of MDA-231 breast cancer cells stably transfected with DNA constructs of pIRES2-EGFP (green fluorescent protein) expressing human BSP (hBSP) cDNA (231BSP) under a CMV promoter, or with an antisense sequence of hBSP cDNA (231BSPAS), or with an empty vector as a control (231EV). These 3 cell groups were selected for neomycin resistance using G418 and analyzed by flow cytometry for GFP expression. The resultant cultured cells expressed different levels of hBSP as detected by RT-PCR and Western blot. Among the three, 231BSP expressed the highest levels of hBSP while 231BSPAS expressed the lowest. The capacity of the tumor cells to metastasize to bone was determined in nude mice (5 in each group) by intra-cardiac injection of the cells from the 3 different groups. Four weeks after inoculation, radiological examination revealed that all the 5 mice in the 231BSP cell group had developed osteolytic bone metastases. In the 231BSPAS group only 1 mouse demonstrated metastatic bone lesions while 3 out of 5 mice in the control group (231EV) developed metastatic lesions in the bone. These results strongly suggest that BSP over-expression in human tumor cells can enhance bone metastasis of MDA-231 cells whereas repressed expression of BSP, using antisense BSP cDNA, inhibits this effect in a mouse model.
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PMID:Over-expression of bone sialoprotein enhances bone metastasis of human breast cancer cells in a mouse model. 1296 84

PC-SPES is an eight herbal mixture that was shown to have activity against prostate cancer. Recently, we purified oridonin from Rabdosia rubescens, one component of PC-SPES, by high performance liquid chromatography (HPLC). The ability of oridonin to inhibit the proliferation of cancer cells was examined by MTT assay. Oridonin effectively inhibited the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138) with ED50s ranging from 1.8 to 7.5 micro g/ml. TUNEL assay and cell cycle analysis showed that oridonin induced apoptosis and G0/G1 cell cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in LNCaP and NCI-H520 cells in a p53-dependent manner. Interestingly, when p53 was suppressed by over-expression of E6 from human papilloma virus type 16 (HPV-16), these cells lost their sensitivity to oridonin-induced growth inhibition and apoptosis. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies and probably represents one of the major, active components of PC-SPES.
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PMID:Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. 1296 3

Bone metastasis is commonly found in prostate cancer (PC) patients. Although the mechanisms for the recurrence of bone metastasis-derived PC during medical or surgical castration therapy are still unclear because of the lack of suitable experimental models, one hypothesis is that enhanced androgen receptor (AR) signaling causes androgen-refractory PC growth. To test this hypothesis, we first established a novel androgen-refractory MDA PCa 2b cell subline, MDA PCa 2b-hr, which was generated in vitro from bone metastasis-derived, androgen-dependent MDA PCa 2b human PC cells after approximately 35 weeks of growth suppression by androgen-depletion treatment to mimic the clinical PC recurrence during androgen-ablation therapy. The changes of the androgen responsiveness of growth and the AR expression levels during the transition from an androgen-dependent to androgen-refractory proliferative phase through a temporal growth-suppressed phase precisely paralleled that of the basal growth rate. Furthermore, the androgen-refractory growth of MDA PCa 2b-hr cells in androgen-depleted medium was suppressed by an antiandrogen, bicalutamide. Next, we established nude mouse xenograft models to clarify whether AR signaling in MDA PCa 2b-hr cells is also enhanced in vivo. Both the MDA PCa 2b and MDA PCa 2b-hr tumors grew in gonadally intact mice, but only the MDA PCa 2b-hr tumors grew in castrated mice. The growth rate of MDA PCa 2b-hr tumors was significantly higher in gonadally intact mice than in castrated mice. Treatment with dehydroepiandrosterone pellets, which produced clinical castration levels of serum testosterone, accelerated the MDA PCa 2b-hr but not MDA PCa 2b tumor growth in castrated mice and increased blood prostate-specific antigen levels in castrated mice bearing MDA PCa 2b-hr tumors but not in mice bearing MDA PCa 2b tumors. Our data suggest that the enhanced AR signaling should be closely correlated with the androgen-refractory growth of human bone metastasis-derived PC, which might come to use adrenal androgens remaining in the blood even after castration therapy and warrant the continuation of hormone therapy for the recurrent PC.
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PMID:Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline. 1450 Apr 4

A disintegrin and metalloproteases (ADAMs) are proteins that contain both a disintegrin and metalloprotease domain and have potential implications for the metastasis of human cancer cells via cell adhesion and protease activities. In this study, we analyzed the expression levels of ADAM-9, ADAM-10 and ADAM-17 (TNF-alpha converting enzyme, TACE), and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic tumor cell lines as well as in clinical patient materials (BPH and tumor tissue samples). Human prostatic tumor cell lines (MDA PCa 2b, LNCaP-C33, -C51, -C81, -Pro5, -Ln3, -C4-2, PC3, and DU145) showed varied levels of expression for ADAM-9, -10 and -17 mRNA. A strong expression of ADAM-17/TACE was further revealed by Western blot analysis in prostatic tumor cell lines. In the case of clinical material, all the tumor samples (8/8) revealed the expression of ADAM-9, -10, and -17 compared to the specimens of benign prostatic hyperplasia (BPH) where 80% of (8/10) samples showed the expression of ADAM-9, 86% (6/7) of ADAM-10, and 30% (3/10) of ADAM-17/TACE. Interestingly, expression of a potent inhibitor of ADAM-17 (TIMP-3) was not detected in any prostatic tumor cell lines (0/9), while TIMP-3 expression was detected in 82% (9/11) of BPH samples. Androgen-sensitive LNCaP-C33 cells exhibited differences in ADAMs regulation by 5alpha-dihydrotestosterone (DHT), while such differences were not detectable in androgen-independent LNCaP-C81 cells. These results suggest that an inverse expression pattern of ADAM-17/TACE and TIMP-3, and the regulation of ADAMs with DHT might play an important role in the pathogenesis of prostate cancer.
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PMID:Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. 1453 78


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