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)

Androgen deprivation therapy causes a paradoxical elevation of matrix metalloproteinases (MMPs) including MMP-9 resulting in aggressive tumor phenotype in many patients with prostate cancer. In this study, we have evaluated a novel antisense phosphorodiamidate Morpholino oligomer (PMO) targeted against MMP-9 in models of angiogenesis and in human prostate xenograft in athymic mice. The treatment of androgen-independent DU145 human prostate cells with a 21-mer MMP-9 antisense PMO caused a dose-dependent inhibition of cell proliferation compared to scrambled or MMP-2 antisense PMO at similar concentrations. This was associated with decreases in MMP-9 expression, gelatinolytic activity and increased stability of the insulin-like growth factor-binding protein (IGFBP-3), a proapoptotic factor and MMP-9 substrate. In vitro invasion assays revealed a 40-60% inhibition of DU145 cell invasion in the presence of 25 microM MMP-9 antisense PMO. A significant decrease in endothelial cell migration and vascularization was observed in the Matrigel plug assay in mice when treated intraperitoneally with 300 microg/day MMP-9 antisense for 21 days. In the highly vascular DU145 tumor xenografts, MMP-9 inhibition caused decreased tumor growth with regression in 50% of the animals. Histological analysis revealed increased apoptosis and fibrous tissue deposits in the MMP-9 antisense-treated tumors compared to the scrambled and saline controls. No apparent toxicity or mortality was associated with the MMP-9 PMO treatment. In summary, the MMP-9 antisense PMO inhibited in vitro prostate cancer cell proliferation, invasion and in vivo angiogenesis. These data establish the feasibility of developing a site-directed, nontoxic antisense therapeutic agent for inhibiting local invasion and metastasis.
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PMID:A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity. 1460 68

alpha-Fetoprotein (AFP), known largely as a growth-promoting agent, also possesses a growth inhibitory motif recently identified as an occult epitopic segment of the molecule. This segment, a 34-amino acid stretch termed the growth inhibitory peptide (GIP), has been chemically synthesized, purified, and characterized. The purified 34-mer exhibits complex aggregation behaviors; initially, trimeric oligomers were formed that possess growth inhibitory activity in rodent uterine bioassays. These rodent growth assays have served as a prelude to the anticancer studies that followed. In solution, the trimers convert slowly to dimers containing intrapeptide disulfide bonds; such dimers are inactive in the antigrowth assays. Cysteine-to-alanine analogues of the GIP retain the antigrowth properties, while similar cysteine-to-glycine and cysteine-to-serine analogues demonstrate little, if any, growth regulatory activity. Chemical modifications of the cysteine residues also have little influence on the antigrowth activity of the GIP. Fragments of the 34-mer possess variable growth activities of their own, with an octamer from near the carboxyl terminus displaying estrogen-dependent antigrowth activity similar to that of the 34-mer. It was further observed that the GIP can bind both Zn(2+) and Co(2+); the Co(2+) peptide complex was shown to have a distorted tetrahedral symmetry, involving coordination of two cysteine and two histidine residues. The Zn(2+)-GIP complex had antigrowth activity and did not form the intrapeptide disulfide bond characteristic of the free GIP in aqueous solution. The GIP was tested in vitro for anticancer activity and was found to suppress the growth in 38 of 60 human cancer cell lines, representing nine different cancer types. In vivo studies of the GIP, certain analogues, and its fragments revealed anticancer activities in both isograft and xenograft animal tumor transplants. Furthermore, the 2C --> 2A replacement analogue was active against a breast tumor in vivo and in vitro and a prostate cancer in vitro. Thus, it is proposed that the GIP, its analogues, and its fragment peptides can potentially serve as lead compounds for cancer therapeutics.
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PMID:Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics. 1461 98

The standard form of cell adhesion glycoprotein CD44 is a metastasis suppressor in prostate cancer. However, we previously showed by RT-PCR and Western blotting that cancer overexpresses unique CD44 variant v7-v10 isoforms. Muc18 is another cell adhesion marker reportedly overexpressed by prostate cancer. Matched frozen section-confirmed tumor and benign tissues were harvested from 10 prostatectomy specimens and tumor was microdissected from two lymph node metastases. Tissues were homogenized for RNA preparations, and RT-PCR was performed for the CD44v7-v10 sequence. In cultured prostate cancer cells, we caused RNA interference against CD44v9 and/or Muc18. We used PC3M cells and a derivative cell line called G(s)alpha, that constitutively expresses this G-protein and is more invasive. Lipofection was performed for a green fluorescent protein plasmid and for two 22-mer DNA fragments, cloned into a plasmid expression vector to generate hairpin, interfering dsRNA. Assays for invasion into Matrigel, a basement membrane matrix, were performed in 4-5 experiments. RT-PCR demonstrated expression of a 608 bp band representing CD44v7-v10 or a 638 bp band of CD44v6-v10 in prostate cancer tissues and metastases but not benign tissue. Cultured G(s)alpha cells overexpressed CD44v9 by comparison with PC3M cells. At 90 h after 6-hour lipofection, protein silencing was evident by Western blots. Silencing the CD44v9 expression reduced invasiveness into Matrigel to 21.6+/-7.0% in PC3M cells (P<0.001) and 31.2+/-18.3% in G(s)alpha cells (P=0.001), compared to cells exposed to transfection vehicle alone. Silencing Muc18 expression reduced invasiveness to 76.9+/-13.5% of the control value in PC3M cells (P<0.05) and 84.8+/-29.9% in G(s)alpha cells (P=0.18). Prostate cancer invasion is facilitated more by its overexpression of CD44 variant 9 than by Muc18. Its relative overexpression by G(s)alpha cells is a novel finding, suggesting a link between signal transduction and cell adhesion marker expression.
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PMID:Prostate cancer invasion is influenced more by expression of a CD44 isoform including variant 9 than by Muc18. 1510 4

The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate tissue is very attractive because prostate is not a vital organ beyond the reproductive years. CD4 T cells play an important role in the development of antitumor immune responses, yet the identification of naturally processed MHC Class II-restricted epitopes derived from prostate differentiation antigens has not been described. To facilitate the search for prostate-specific antigen (PSA)-derived MHC class II-restricted peptides, we immunized mice transgenic for HLA-DRB1*1501 with human PSA and showed a robust dose-dependent immune response to the antigen. Screening a library of overlapping 20-mer peptides that span the entire PSA sequence identified two 20-mer peptides, PSA(171-190) and PSA(221-240), which were responsible for this reactivity. Immunization of DR2b transgenic mice with these peptides induced specific responses to the peptide and whole PSA. Identified peptides were used to stimulate CD4 T cells from HLA-DRB1*1501+ patients with a rare condition, granulomatous prostatitis, and who seem to have a preexisting immune response directed against the prostate gland. We previously showed a linkage of granulomatous prostatitis to HLA-DRB1*1501, suggesting that this disease may have an autoimmune etiology. Peptide-specific CD4 T-cell lines were generated from the peripheral blood of these patients as well as one patient with prostate cancer. These lines also recognized whole, processed PSA in the context of HLA-DRB1*1501. This study will be instrumental in understanding the interaction between circulating self-reactive T cells, organ-specific autoimmunity, and antitumor immune response. The use of these peptides for the immunotherapy of prostate cancer is under investigation.
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PMID:Identification of HLA-DRB1*1501-restricted T-cell epitopes from prostate-specific antigen. 1583 32

Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.
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PMID:Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer. 1595 58

Chemotherapy, hormonal therapy, or surgery may cause devastating toxic or other side effects. Androgen receptors (ARs) in the cytoplasm are activated by binding with androgen. Androgen-activated ARs bind to a specific genomic DNA sequence, the androgen-responsive element (ARE), and initiate gene expression at the transcriptional level. Even without androgen activation, ARs may have a role in androgen-refractory prostate cancer. Thus, inhibition of AR activity may have therapeutic value. We applied a genetic reporter of the Dual-Luciferase Assay System to test whether a short double-stranded genomic DNA containing prostate-specific antigen (PSA) ARE sequence as decoy DNA would inhibit the function of activated AR. A 21-mer phosphorothioated PSA ARE decoy DNA was synthesized, with a plasmid vector containing the PSA promoter upstream from a luciferase gene, the reporter gene. The promoter and reporter were co-transfected into a human prostate cancer cell line PC3-M with the aid of Lipofectamin 2000. After 24 hr exposure to androgens, the cells were lysed and luciferase activity measured to determine the ARE decoy inhibitory effect on the function of ARs. Luciferase activity was reduced significantly in the ARE decoy transfected cells but not with inactive control decoy. The results demonstrate that ARE decoy DNA can effectively suppress androgen-activated ARs in prostate cancer cells and indicate the potential utility of decoy DNA for developing a novel therapy for prostate cancer.
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PMID:Decoy androgen-responsive element DNA can inhibit androgen receptor transactivation of the PSA promoter gene. 1608 84

Survivin is an antiapoptotic gene, which is overexpressed in most human tumors and involved in mitotic checkpoint control. Recent evidence points to an essential role for heat shock protein 90 (Hsp90) in survivin function regulation. Although the survivin-Hsp90 association may promote tumor cell proliferation, it may also suggest new opportunities for the design of novel anticancer approaches. We evaluated the effect of small interfering RNA (siRNA)-mediated inhibition of survivin on the proliferative potential of prostate cancer cells and their sensitivity to the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). Human androgen-independent prostate cancer cell lines (DU145 and PC-3) were transfected with four 21-mer double-stranded siRNAs (100 nmol/L) directed against different portions of survivin mRNA. After transfection, cells were collected and analyzed for survivin mRNA and protein expression, cell proliferation rate, ability to undergo apoptosis, and sensitivity to 17-AAG. Transfection of prostate cancer cells with siRNAs induced a variable extent of inhibition of survivin mRNA expression (39-60% compared with controls), which was paralleled by a 38% to 75% reduction in survivin protein abundance. The three siRNAs able to induce the greatest inhibition of survivin expression also significantly reduced cell proliferation and enhanced the rate of apoptosis, with a concomitant increase in caspase-9 activity. Sequential treatment with siRNA and 17-AAG induced supra-additive antiproliferative effects in all cell lines, with an enhanced caspase-9-dependent apoptotic response. These findings suggest that combined strategies aimed at interfering with the survivin-Hsp90 connection may provide novel approaches for treatment of androgen-independent prostate cancer.
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PMID:Silencing of survivin gene by small interfering RNAs produces supra-additive growth suppression in combination with 17-allylamino-17-demethoxygeldanamycin in human prostate cancer cells. 1643 77

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-alpha) (MR1) and its binding site, the epidermal growth factor receptor (EGFR) (MR2), are efficacious against PC-3 and LNCaP prostate tumors. To enhance activity and aid in simultaneous delivery, "bispecific" 39-mer oligos were constructed containing portions of both MR1 and MR2 sequences. The first pair contained truncated sequences recognizing TGF-alpha and EGFR mRNA binding sites, about their respective AUG initiation codons. These bispecifics differ in their 5' to 3' tandem orientation (TGF-alpha/EGFR [MR12] and EGFR/TGF-alpha [MR21] sequences). A second pair was constructed having complementary sequences for EGFR and bcl-2 (EGFR/bcl-2 [MR24] and bcl-2/EGFR [MR42]). All bispecifics were tested in vitro against PC-3 and LNCaP prostate tumor cells, and compared to mono-specific oligos from which they were derived. The purpose of this study was: (1) to evaluate bispecific antitumor activity; (2) to identify dominant sequences; (3) to identify effects of binding site orientation; and (4) to determine whether bispecifics are more effective when targeting one versus different growth-dependent pathways. Comparisons were made between oligos tested against either PC-3 or LNCaP cells incubated for 2 d with the agents followed by 2 d in their absence. The first PC-3 cell experiment demonstrated that bispecific MR12 and MR21 oligos are at least as effective as their mono-specific counterparts and that the MR21 bispecific orientation is more effective than the MR1 mono-specific by 64% (p = 0.014). It also suggested that the sequence directed against EGFR contributed most to bispecific activity, particularly in the MR21 orientation. In a second PC-3 study a second bispecific pair of 37-mer oligos was constructed containing bases complementary to mRNA encoding EGFR and the apoptosis-associated protein bcl-2 (MR4). MR24 was constructed with the EGFR complementary site at the 5' end (EGFR/bcl-2), and MR42, containing the opposite orientation (bcl-2/EGFR). Each contained the dominant EGFR activity identified previously. MR1, MR2, MR4, MR12, MR21, MR24, and MR42 (1X and 2X in concentration) were cultured with cells and compared to controls. Each oligo significantly inhibited growth of PC-3 cells. MR42 was most effective and significantly better than MR1 (p = 0.0128), MR2 (p = 0.021), MR4 (p = 0.0002), and MR12 (p = 0.0032). 2X MR24 and 2X MR42 were better than their 1X concentration counterparts, but the differences were not significant. In a similar experiment MR1, MR2, MR4, MR12, MR21, MR24, and MR42 were cultured with LNCaP cells and compared to lipofectin-containing controls. Each oligo significantly inhibited the growth of LNCaP cells. Again, MR42 was most effective and significantly better than MR2 (p = 0.021) and MR4 (p = 0.038). MR24 was significantly better than MR2 (p = 0.048). Bispecific oligos are a significant advance in antisense technology and could play a role in treating prostate cancer, particularly if combined with traditional chemotherapeutics.
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PMID:Bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors. 1784 43

The mechanisms of functional repression of the androgen receptor (AR) are crucial for the regulation of genes involved in physiological development as well as for the progression of prostate cancer. To date, only two in vivo inhibitors of AR-mediated transcription have been identified: DAX-1 and SHP (small heterodimer partner). SHP is a regulatory nuclear receptor (NR) that lacks DNA-binding and activation domains. Using X-ray crystallography, the interaction between peptide segments of the SHP repressor containing LxxLL-like motifs and the ligand-binding domain of AR have been investigated. Under the crystallization conditions used, it was found that of the three NR Boxes present in the SHP protein sequence, only NR Box 2 (LKKIL motif) formed a complex with AR. Determination of the crystal structure revealed that ten amino acids of the SHP peptide (14-mer) are ordered through interactions with AR. Two side chains make unique interactions that were not reported for other AR-peptide complexes. The NR Box 2 of SHP binds to an adaptable hydrophobic groove on the surface of AR in a fashion observed for other NR-LxxLL-like complexes. Comparisons of AR structures bound to coactivator peptides and the SHP peptide revealed structural similarity of their binding sites, suggesting that transcriptional AR activity may be inhibited by SHP by competing with AR coactivators.
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PMID:Interaction between the androgen receptor and a segment of its corepressor SHP. 1800 36

The ability to regulate the cellular homeostasis of a higher organism through tight control of apoptosis and cell division is crucial for life. Dysregulation of these mechanisms is often associated with cancerous phenotypes in cells. Optimal cancer therapy is a fine balance between effective cancer cell killing and at the same time minimizing, or avoiding, damage to the surrounding healthy tissue. To obtain this, it is necessary to identify and inhibit molecular targets on which the cancer cells are strongly dependent. Survivin represents such a target, and it has been published previously that peptide vaccines, the small-molecule YM155, and the antisense molecule LY2181308/ISIS23722, via different mechanisms, have been used as survivin inhibitors. In this article, a new potent antisense inhibitor of survivin, SPC3042, is presented, and the properties of SPC3042 are compared with the previously published antisense drug, LY2181308/ISIS23722. SPC3042 is a 16-mer locked nucleic acid (LNA) oligonucleotide and designed as a fully phosphorothiolated gapmer containing 7 LNA nucleotides in the flanks. The LNA nucleotides in SPC3042 provide nuclease stability and higher potency for survivin mRNA inhibition compared with earlier generations of antisense reagents. It is shown that the down-regulation of survivin with SPC3042 leads to cell cycle arrest, pronounced cellular apoptosis, and down-regulation of Bcl-2. It is also shown that SPC3042 is a sensitizer of prostate cancer cells to Taxol treatment in vitro and in vivo.
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PMID:SPC3042: a proapoptotic survivin inhibitor. 1879 Jul 54


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