共查询到20条相似文献,搜索用时 15 毫秒
1.
O'Connor K Gill C Tacke M Rehmann FJ Strohfeldt K Sweeney N Fitzpatrick JM Watson RW 《Apoptosis : an international journal on programmed cell death》2006,11(7):1205-1214
Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic
options. Highly substituted ansa-titanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives
of this study are to examine the effects of these titanocene compounds on prostate cancer cells.
Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin.
Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome
C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal
microscopy.
These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant
effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition
of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating
a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent
apoptosis following treatment with all the titanocene compounds.
This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over
cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer. 相似文献
2.
Among males, prostate cancer has become the second leading cause of cancer-related deaths in North America, with similar trends
in many Western and developing countries. One way to control prostate cancer is through chemoprevention, which refers to the
administration of synthetic or naturally occurring agents to block, reverse, or delay the process of carcinogenesis. For a
variety of reasons, the most important of which is human acceptance, for chemopreventive intervention, naturally occurring
diet-based agents are preferred. Prostate cancer is an ideal candidate disease for chemopreventive intervention, because it
grows very slowly, likely for decades, before symptoms arise and a diagnosis is finally established, it has a long latency
period, and it is typically diagnosed in men >50 years of age. Most chemopreventive agents are antioxidant in nature. We have
been defining the usefulness of dietary anti-oxidants for chemoprevention of prostate and other cancers. It is increasingly
appreciated that some of these dietary anti-oxidants are nature’s gift molecules endowed with cancer preventive and therapeutic
properties. This review will focus on prostate cancer chemopreventive effects of polyphenolic anti-oxidants derived from green
tea and pomegranate. It is a challenge to custom-tailor these gift molecules as cocktails in concentrations that can easily
be consumed by humans for delaying prostate and other cancers. 相似文献
3.
Gududuru V Hurh E Sullivan J Dalton JT Miller DD 《Bioorganic & medicinal chemistry letters》2005,15(18):4010-4013
In our continuing efforts to develop novel chemotherapeutic agents for prostate cancer, recently we reported the discovery of 2-arylthiazolidine-4-carboxylic acid amides (ATCAAs) as a new class of cytotoxic agents. Several of them were very effective in killing specific human prostate cancer cell lines with low/sub-micromolar cytotoxicity and high selectivity against control cells in our sulforhodamine B assay. Encouraged with these preliminary results, we decided to further optimize this new scaffold to enhance the potency and selectivity. Current work describes the synthesis, SAR, and biological evaluation of new compounds for their ability to inhibit the growth of five human prostate cancer cell lines. The cytotoxicity data demonstrated that ATCAAs are sensitive to simple modifications or changes, which allowed us to understand the minimum structural requirements of this class of compounds to exhibit potent and selective anticancer activity against prostate cancer cells. 相似文献
4.
Trachtenberg J 《Reviews in urology》2001,3(Z3):S23-S28
The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available compounds with new applications; and 3) new compounds applied to established indications. The novel compounds target specific receptor sites of cancer pathways and attack cancer cells with less effect on normal tissue. Earlyphase trials with compounds targeting the endothelin-A and EGF receptors have shown encouraging results in hormone-refractory prostate cancer. In addition, the Early Prostate Cancer Trial of over 8000 men is currently underway to determine the benefit of adjuvant androgen ablation with bicalutamide in men with localized prostate cancer. Early results show a significant 42% reduction in the progression of the disease in the bicalutamide treatment arm. Further, in large, phase 3 clinical trials in patients needing androgen ablation, the GnRH antagonist abarelix caused no testosterone surge and demonstrated a significantly more rapid decline in serum testosterone to the castrate level than did an LHRH agonist analogue. Abarelix should thus have application as a monotherapy in patients who need a rapid onset of action or are at high risk of complications from the clinical flare seen with LHRH agonists. Abarelix also uniquely caused a sustained decline in serum FSH levels, which have been shown in vitro to stimulate prostate cancer cell growth. If these favorable effects can be duplicated in patients, abarelix might also offer a survival benefit. 相似文献
5.
Synthesis and antiproliferative activity of 2-aryl-4-oxo-thiazolidin-3-yl-amides for prostate cancer
Gududuru V Hurh E Dalton JT Miller DD 《Bioorganic & medicinal chemistry letters》2004,14(21):5289-5293
We have previously described serine amide phosphates (SAPs) as a novel class of cytotoxic agents for prostate cancer. Several of them showed potent cytotoxicity against human prostate cancer cell lines, but were not selective in non-tumor cells. To improve the selectivity and further enhance the potency, we designed a new series of 2-aryl-4-oxo-thiazolidin-3-yl amides. The current work describes synthesis, SAR, and biological evaluation of these compounds for their ability to inhibit the growth of prostate cancer cells. The antiproliferative effects of synthesized compounds were examined in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, and TSU), and in RH7777 cells (negative controls). From this study, three potent compounds (8, 20, and 21) have been detected, which are effective in killing prostate cancer cells with improved selectivity compared to SAPs. 相似文献
6.
Inflammation has been implicated for some time as a potential aetiological agent in human prostate cancer. Viral and bacterial infections or even chemical carcinogens such as those found in cooked meat have been proposed as the inflammatory stimuli, but the mechanism of cancer induction is unknown. Recent information about gene expression patterns in normal and malignant epithelial stem cells from human prostate provides a new hypothesis for inflammation-induced carcinogenesis. The hypothesis states that in the stem cells located in the basal cell compartment of the prostate, activated prostate epithelial stem cells acquire a survival advantage, by expressing one of more of the same cytokines such as IL6. The establishment of one or more autocrine signalling loops results in an expansion of these cells in the absence of inflammation, as a potential first stage in the development of the tumour. 相似文献
7.
Cadmium and cancer of prostate and testis 总被引:13,自引:0,他引:13
8.
前列腺癌是中国发病率增长最快的男性肿瘤,抗雄激素治疗耐药是导致前列腺癌患者预后差的主要原因。因此,解决耐药性难题是前列腺癌转化研究的关键问题。哺乳动物细胞利用泛素-蛋白酶体系统实现蛋白质的靶向降解。因此,前列腺癌中关键的癌基因如雄激素受体(AR)的上游泛素化调控因子(如去泛素化酶)是潜在的治疗靶点。然而,这些酶具有较广的底物谱系,存在脱靶的可能性。近来,基于泛素-蛋白酶体系统开发的蛋白质降解靶向嵌合体(proteolysis-targeting chimeras,PROTAC)技术是最具前景和革命性的新型抗癌药物研发技术,能够利用特定E3泛素连接酶对靶蛋白进行降解而不影响其他底物。与传统小分子抑制剂相比,PROTAC分子在克服耐药性以及针对不可成药的靶点方面拥有巨大优势。目前,针对AR的PROTAC降解剂已在II期临床取得了成功,靶向蛋白质泛素化及降解途径的新技术将有望为前列腺癌的临床治疗带来新的突破。 相似文献
9.
The use of genetically engineered mouse models of prostate cancer for nutrition and cancer chemoprevention research 总被引:1,自引:0,他引:1
Klein RD 《Mutation research》2005,576(1-2):111-119
The ability to modify the expression of specific genes in the mouse through genetic engineering technologies allows for the generation of previously unavailable models for prostate cancer prevention research. Although animal models have existed for some time for the study of prostate cancer prevention (primarily in the rat), it is uncertain if the mechanisms that drive prostate carcinogenesis in these models are relevant to those in human prostate cancer. Cell culture studies are of limited usefulness because the conditions are inherently artificial. Factors such as relevant physiologic concentrations and metabolism of putative chemoprevention compounds are difficult to model in an in vitro system. These studies also preclude the types of interactions known to occur between multiple cell types in vivo. In addition, all prostate cancer cell lines are already highly progressed and are not representative of the type of cells to which most preventive strategies would be targeted. Due to the advent of genetically engineered mouse (GEM) models, we now have models of prostate cancer that are dependent on molecular mechanisms already implicated in human prostate carcinogenesis. With these models we can perform a variety of experiments that could previously only be done in cell culture or in prostate cancer cell line xenografts. The currently available GEM models of prostate cancer have been extensively reviewed therefore, this review will focus on the types of models available and their usefulness for various types of preclinical studies relevant to prostate cancer prevention. 相似文献
10.
Haney KM Zhang F Arnatt CK Yuan Y Li G Ware JL Gewirtz DA Zhang Y 《Bioorganic & medicinal chemistry letters》2011,21(18):5159-5163
Prostate cancer is a leading cause of death among males in the United States. As the chemokine receptor CCR5 is over-expressed in more aggressive forms of prostate cancer, and is also a critical receptor in inflammation, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. Anibamine, a natural product CCR5 antagonist, provides a unique molecular scaffold for the generation of novel analogs with possible anti-prostate cancer activity. A series of analogs of anibamine were designed, synthesized and tested against several prostate cancer cell lines. The analogs all acted as CCR5 antagonists at micromolar range affinity to the receptor while their anti-proliferative activity varied depending on the cell line type and their chemical structural properties. Further basal cytotoxicity characterization on these compounds indicated some of them may be suitable for in vivo studies. 相似文献
11.
Prostate cancer is a long latency type of tumor that usually develops in men older than 50 years of age. Prostate epithelial neoplasia (PIN), the initial malignant lesion, progresses to invasive carcinoma over the course of years. Because of the particular features of prostate carcinogenesis, this type of tumor may represent a paradigm for cancer prevention. Several clinical trials have evaluated the effect of different compounds on prostate tumor development, including finasteride, selenium, vitamin E, and carotenes. Although some results are promising, no conclusive data have been achieved as to recommend any of these compounds as preventive agents. Results from some trials, such as SELECT, where supplementation of selenium and/or vitamin-E was used, have been rather disappointing. However, many novel chemopreventive agents that target different cancer-related pathways are being developed lately. Appropriate animal models (in particular, genetically modified mice) are being used to assess the efficacy of these novel compounds. The transgenic adenocarcinoma of the mouse prostate (TRAMP) model has been validated as an accurate model to test a variety of preventive agents. Genistein, alpha-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib, and green tea polyphenols have been shown to prevent prostate cancer development in TRAMP mice. In conclusion, new chemopreventive compounds which are effective in animal models are likely to be tested soon in clinical trials, with the final goal of reducing prostate cancer incidence in men. 相似文献
12.
BACKGROUND: DNA vaccines have been shown to be an effective approach to induce antigen-specific cellular and humoral immunity. However, the lower immune intensity in clinical trials limits the application of DNA vaccine. Here we intend to develop a new DNA vaccine based on prostate stem-cell antigen (PSCA), which has been suggested as a potential target for prostate cancer therapy, and enhance the DNA vaccine potency with heat shock proteins (HSPs) as adjuvant. METHODS: A series of DNA plasmids encoding human PSCA, human HSP70 and their conjugates was constructed and injected into male mice intramuscularly (i.m.). To evaluate the immune responses and therapeutic efficacy of these plasmids, major histocompatibility complex (MHC)-restricted PSCA and HSP70-specific epitopes were predicted and a mouse model with a human PSCA-expressing tumor was constructed. RESULTS: The result showed that mice vaccinated with PSCA-HSP plasmids generated the strongest PSCA-specific CD8+ T-cell immune response, but the CD4+ TH1 and TH2 cell immune responses were similar with those vaccinated with other HSP-adjuvant PSCA plasmids or only PSCA DNA. The immunity of HSP70 was also observed and the mice i.m. injected with PSCA+ HSP mixed plasmids generated the lowest anti-HSP antibodies. Furthermore, these vaccinations inhibited the growth of PSCA-expressing tumors and prolonged mouse survival. CONCLUSIONS: These observations emphasize and extend the potential of the human HSP70 gene as adjuvant for DNA vaccines, and the vaccine based on PSCA and HSP70 is of potential value for treating prostate cancer. 相似文献
13.
Avila DM Zoppi S McPhaul MJ 《The Journal of steroid biochemistry and molecular biology》2001,76(1-5):135-142
The actions of androgens, principally testosterone and 5alpha-dihydrotestosterone, are mediated by a specific receptor protein, the androgen receptor (AR), which is encoded by a single-copy gene located on the human X-chromosome. This receptor protein is a prototypical member of the nuclear receptor family and modulates a range of processes during embryogenesis and in the adult. During embryogenesis, normal AR function is critical to the development of the male phenotype and defects of the AR cause a range of phenotypic abnormalities of male sexual development. Complete loss of AR function has been traced to a number of distinct types of genetic events, including abnormalities of mRNA splicing, the introduction of premature termination codons, and amino acid substitution mutations. An interesting subset of mutations is that in which the AR is completely undetectable using sensitive immunoassays. In all instances, these functional abnormalities are associated with a phenotype of complete androgen insensitivity (complete testicular feminization). By contrast, partial defects of AR function are almost invariably caused by amino acid substitutions within the DNA- and hormone-binding domains of the receptor protein. Such partial defects of receptor function may be caused by changes in either receptor function or receptor abundance.The alterations of AR function and expression that have been characterized in clinical prostatic cancers and in prostate cancer cell lines differ in several important respects. A number of studies have documented the emergence of considerable heterogeneity of AR expression at early stages in the development of prostate cancer. Despite these early changes of AR expression, a substantial body of information suggests that the AR is expressed in advanced forms of prostate cancer, in some cases as the result of amplification events. While infrequent in localized tumors, mutations of the AR have been identified in a number of advanced prostatic cancers and in some instances appear to alter the ligand specificity of the AR. Finally, it appears that other signaling pathways can act to influence AR function. 相似文献
14.
Gududuru V Hurh E Durgam GG Hong SS Sardar VM Xu H Dalton JT Miller DD 《Bioorganic & medicinal chemistry letters》2004,14(19):4919-4923
We describe herein synthesis, SAR, and biological evaluation of a novel series of cytotoxic serine amide phosphates (SAPs) for prostate cancer. These compounds were tested for their cytotoxicity in five human prostate cancer cell lines (DU-145, PC-3, LNCaP, PPC-1, and TSU), and in CHO and RH7777 cells (negative controls). Comparison of anticancer effects of these compounds with a standard chemotherapeutic agent 5-fluorouracil shows that they are very effective in killing prostate cancer cells with low micromolar cytotoxicity and provide us a new lead for the development of drugs for prostate cancer. 相似文献
15.
Marisa Cabeza Alejandro Posada Araceli Sánchez-Márquez Yvonne Heuze Isabel Moreno Juan Soriano 《Journal of enzyme inhibition and medicinal chemistry》2016,31(1):53-62
The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17β-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Δ4-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17β-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17β-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia. 相似文献
16.
Carruba G 《Journal of cellular biochemistry》2007,102(4):899-911
Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression. Interestingly, many genes encoding for steroid enzymes are polymorphic, although only a few studies have supported their relation with risk of prostate cancer. In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells. Although the mechanisms underlying the hormonal induction of prostate cancer in experimental animals remain uncertain, there is however evidence to support the assumption that long term administration of androgens and estrogens results in an estrogenic milieu in rat prostates and in the ensuing development of dysplasia and cancer. Both androgen and estrogen have been reported to stimulate proliferation of cultured prostate cancer cells, primarily through receptor-mediated effects. As for estrogens, the two major receptor types, ERalpha and ERbeta, are expressed in both normal and diseased human prostate, though with a different cellular localization. Since these two receptors are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, it is likely that an imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells. In prostate cancer, ERbeta activation appears to limit cell proliferation directly or through ERalpha inhibition, and loss of ERbeta has been consistently associated with tumor progression. Several splicing variants of both ERalpha and ERbeta exist. Little is known about their expression and function in the human prostate, although reciprocal regulation and interaction with gene promoter both warrant further investigation. In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest. 相似文献
17.
18.
Ide H Hatake K Terado Y Tsukino H Okegawa T Nutahara K Higashihara E Horie S 《Human cell》2008,21(1):1-6
Recent evaluation of human prostate tissues has shown predominantly high expression of the macrophage colony-stimulating factor receptor in prostatic intra-epithelial neoplasia or prostate cancer. However, the expression of its ligand, the macrophage colony-stimulating factor (M-CSF), and the biological role of this signaling in prostate cancer has not been analyzed. In this research we determined the relationship of serum M-CSF level to clinical parameters of prostate cancer progression. We measured the serum level of M-CSF in 170 patients with histologically confirmed prostatic adenocarcinoma and in 54 patients in whom prostate cancer was not detected. We also investigated the M-CSF expression in prostate cancer tissues by immunohistochemistry. The serum levels of M-CSF in bone metastatic prostate cancer patients was significantly higher than those in non-metastatic patients, while M-CSF did not differ with regards to histological grade, Gleason score or local tumor progression. M-CSF expression was detected in prostate cancer cells themselves by immunohistochemistry. These results suggest that M-CSF may have a functional role in prostate cancer progression. 相似文献
19.
Tang H Brown M Ye Y Huang G Zhang Y Wang Y Zhai H Chen X Shen TY Tenniswood M 《Biochemical and biophysical research communications》2003,307(1):8-14
To identify inhibitors of the intrinsic N-acetylated alpha-linked acidic dipeptidase (NAALADase) activity of prostate specific membrane antigen (PSMA) that may be useful for targeting imaging agents or chemotherapeutic drugs to disseminated prostate cancer, analogs of the tetrahedral transition state for hydrolysis of the natural substrate, N-acetylaspartylglutamate (NAAG), were synthesized. These compounds were assayed for their ability to inhibit the membrane-associated enzyme isolated from LNCaP prostate cancer cells. Active inhibitors were further assayed for their cytotoxicity and membrane binding. We have identified nine compounds, including fluorescent and iodine-labeled conjugates, which inhibit NAALADase enzyme activity with IC(50)s at, or below, 120nM. The binding of these compounds to the cell surface of viable LNCaP prostate tumor cells appears to be specific and saturable, and none of the compounds alter the cell cycle kinetics or induce apoptosis in LNCaP cells, suggesting that they are relatively innocuous and are suitable for targeting imaging agents or cytotoxic drugs to disseminated prostate cancer. 相似文献
20.
Polyamines and prostatic cancer 总被引:7,自引:0,他引:7
Schipper RG Romijn JC Cuijpers VM Verhofstad AA 《Biochemical Society transactions》2003,31(2):375-380
The importance of polyamines in prostatic growth and differentiation has prompted studies to evaluate the clinical relevance of the ornithine decarboxylase/polyamine system in prostatic cancer. These studies show that differences in biological behaviour of prostatic (cancer) cells are associated with changes in polyamine levels and/or the activity of their metabolic enzymes. Faulty antizyme regulation of polyamine homoeostasis may play an important role in the growth and progression of prostatic carcinoma. Treatment of human prostate carcinoma cells with inhibitors of polyamine metabolic enzymes or polyamine analogues induces cell growth arrest or (apoptotic) cell death. Our recent in vitro studies using conformationally restricted polyamine analogues show that these compounds inhibit cell growth, probably by inducing antizyme-mediated degradation of ornithine decarboxylase. Sensitivity of human prostate cancer cells for these compounds was increased in the absence of androgens. These results suggest that these analogues might have chemotherapeutic potential in case prostatic cancer has become androgen-independent. Pilot data in an in vivo model show that these analogues have effects on tumour cell proliferation, vascularity, blood perfusion and tissue hypoxia. Overall, these studies show that polyamines may serve as important biomarkers of prostatic malignancy and provide a promising target for chemotherapy of prostatic cancer. 相似文献