Tau oligomers accumulation sensitizes prostate cancer cells to docetaxel treatment.

Purpose: Human tau is a highly dynamic, multifunctional protein expressed in different isoforms and conformers, known to modulate microtubule turnover. Tau oligomers are considered pathologic forms of the protein able to initiate specific protein accumulation diseases, called tauopathies. In our study, we investigated the potential association between autophagy and tau oligomers accumulation and its role in the response of prostate cancer cells to docetaxel.

Psychoneuroendocrinoimmunology-based meditation (PNEIMED) training reduces salivary cortisol under basal and stressful conditions in healthy university students: Results of a randomized controlled study.

Background: Meditation represents an effective and safe practice to lower distress and promote well-being. PsychoNeuroEndocrinoImmunology-based Meditation (PNEIMED) is a validated method that can reduce stress-related symptoms and salivary cortisol secretion. To date, few randomised controlled trials (RCTs) have assessed cortisol levels through salivary samples, collected both in the morning phase and during acute mental stress elicitation, in healthy young subjects following brief meditation training.

CXCR4 pharmacogical inhibition reduces bone and soft tissue metastatic burden by affecting tumor growth and tumorigenic potential in prostate cancer preclinical models.

Background: The majority of prostate cancer (Pca) patient morbidity can be attributed to bone metastatic events, which poses a significant clinical obstacle. Therefore, a better understanding of this phenomenon is imperative and might help to develop novel therapeutic strategies. Stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4 have been implicated as regulators of bone resorption and bone metastatic development, suggesting that agents able to suppress this signaling pathway may be used as pharmacological treatments.

Trifluoroibuprofen inhibits α-methylacyl coenzyme A racemase (AMACR/P504S), reduces cancer cell proliferation and inhibits in vivo tumor growth in aggressive prostate cancer models.

Background: α-Methylacyl-CoA racemase (AMACR) participates in the oxidation of branched chain fatty acids and is highly expressed in prostate cancer (PCa). The aims of this study were to verify if the AMACR inhibitor trifluoroibuprofen (TFIP) had anticancer effects and to determine the best route for in vivo administration.

Materials And Methods: In vitro effects of TFIP were verified by using three non-tumour prostate epithelial cell lines, a series of eight PCa cell lines and six cell derivatives.

PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer.

Aberrant activation or 'reactivation' of androgen receptor (AR) during androgen ablation therapy shows a potential cause for the development of castration-resistant prostate cancer. This study tested the hypothesis that PXD101, a potent pan histone deacetylase (HDAC) inhibitor, may prevent onset of castration-resistant phenotype and potentiate hormonal therapy. A panel of human prostate cancer cells with graded castration-resistant phenotype and in vivo models were used to verify this hypothesis.

Increased levels of DNA methyltransferases are associated with the tumorigenic capacity of prostate cancer cells.

DNA methylation might be the earliest somatic genome changes in prostate cancer that also play an important role in the process of tumor invasion, growth and metastasis. In recent years, several inhibitors of DNA methyltransferases (DNMTis) have been developed and evaluated in pre-clinical models and in clinical trials. While these compounds are effective in the treatment of hematological conditions, clinical trials in solid tumors and in prostate cancer have shown limited or no efficacy.

TLR4 and TLR9 Expression in Different Phenotypes of Rhinitis.

Background. Toll-like receptors (TLRs) represent a family of evolutionarily conserved proteins, that represent a fundamental link between innate and adaptive immune responses. Aim.

Azacitidine improves antitumor effects of docetaxel and cisplatin in aggressive prostate cancer models.

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel (DTX) and cisplatin using two models of aggressive prostate cancer, the 22rv1, and PC3 cell lines. Azacitidine shows antiproliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with the absence of acute cell killing in PC3 cells.

Her2 crosstalks with TrkA in a subset of prostate cancer cells: rationale for a guided dual treatment.

Background: To date, no effective therapeutic treatment prevents prostate cancer (PCa) progression to more advanced and invasive disease forms. It has been demonstrated that the simultaneous high expression of p185(HER2) and TrkA might confer a proliferative advantage to PCa cells.

Methods: In this work we verified the crosstalk between TrkA and Her2 signaling pathways and the effects of a combined treatment with Her2 and TrkA inhibitors.

Effects of dutasteride on prostate carcinoma primary cultures: a comparative study with finasteride and MK386.

Purpose: The profound decrease in serum dihydrotestosterone observed with the dual 5alpha-reductase inhibitor dutasteride makes it an attractive agent for prostate cancer therapy. To our knowledge we compared for the first time the antitumor effect of dutasteride with that of the specific 5alpha-reductase-1 inhibitor MK386 and the specific 5alpha-reductase-2 inhibitor finasteride in human prostate primary cultures.

Materials And Methods: Biochemical markers of the cellular response to 5alpha-reductase inhibitors were evaluated in primary cultures of prostate epithelial cancer cells from 54 patients with prostate carcinoma.

Akt down-modulation induces apoptosis of human prostate cancer cells and synergizes with EGFR tyrosine kinase inhibitors.

Background: PTEN is a well-characterized tumor suppressor that negatively regulates cell growth and survival through the modulation of PI3K/Akt pathway.

Methods: In this paper, we investigated the effects of an PI3K/Akt inhibitor, perifosine, in human prostate cancer (PCa) cells analyzing cell proliferation, apoptosis, and the synergy with EGFR inhibitors.

Results: Clinically achievable concentrations of perifosine, as well as Akt gene knockdown, induced a G0/G1 arrest and apoptosis in PTEN defective PCa cells.

Arachidonic acid modulates the crosstalk between prostate carcinoma and bone stromal cells.

Diets high in n-6 fatty acids are associated with an increased risk of bone metastasis from prostate carces (PCa). The molecular mechanism underlying this phenomenon is largely unknown. Arachidonic acid (AA) and its precursor linoleic acid can be metabolized to produce pro-inflammatory cytokines that act as autocrine and paracrine regulators of cancer behavior.

Neuroendocrine transdifferentiation induced by VPA is mediated by PPARgamma activation and confers resistance to antiblastic therapy in prostate carcinoma.

Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western Countries. When prostatectomy fails to eradicate the primary tumor, PCa is generally refractory to all therapeutic approaches. Valproic acid (VPA) is a promising anticancer agent recently assigned to the class of histone deacetylase (HDAC) inhibitors.

Surgical and biologic outcomes after neoadjuvant bicalutamide treatment in prostate cancer.

Objectives: To perform a randomized, prospective, controlled, intention-to-treat study to determine the usefulness of bicalutamide as a neoadjuvant hormonal therapy regimen to surgery in reducing positive surgical margins and modulating epidermal growth factor receptor (EGFR) member's in men with prostate cancer.

Methods: From April 2002 to December 2003, 430 men were diagnosed with prostate cancer. Of these men, 119 with clinical Stage T2-T3a were enrolled.

Gefitinib and bicalutamide show synergistic effects in primary cultures of prostate cancer derived from androgen-dependent naive patients.

We previously demonstrated that the inhibition of the epidermal growth factor receptor (EGFR) signalling affects the endocrine therapy responses of prostate cancer (PCa) cells and that bicalutamide (BCLT) is able to reinforce PI3K activity through mechanisms involving PTEN decrement and EGFR and Her2 activities. The aim of this study was to evaluate if the hormonal therapy with BCLT can affect the EGFR-targeted therapy using primary cultures obtained from 22 human PCa tissues harvested after radical prostatectomy (RP) in patients who received (n=10) BCLT and those that did not (n=12) as neoadjuvant hormone therapy (NHT). We demonstrated that cultures derived from PCa tissues harvested after NHT presented significantly higher EGFR and Her2 levels compared to cultures derived from control patients.

Bicalutamide increases phospho-Akt levels through Her2 in patients with prostate cancer.

Bicalutamide monotherapy is emerging as an alternative in the treatment of locally advanced prostate cancer. However, a significant number of these patients will recur and be in need of second-line therapies. The knowledge of molecular arrangements after pharmacological therapy seems to be a new primary prerequisite to predict the efficacy or the failure of a secondary therapy.

Uncoupling of the epidermal growth factor receptor from downstream signal transduction molecules guides the acquired resistance to gefitinib in prostate cancer cells.

The clinical efficacy of ErbB1 kinase inhibitors is limited by the development of acquired autoresistance. The activation of alternative signaling pathways can contribute to gefitinib resistance. In this study, we demonstrate that the continuous in vitro exposure of the phosphatase and tensin homologue (deleted from chromosome 10)-negative prostate cancer (PC)3 cell line to gefitinib resulted in a sustained growth inhibition of 50% for about 2 months, but afterwards the surviving cells resumed their usual proliferation rate.

In vitro and in vivo effects of bicalutamide on the expression of TrkA and P75 neurotrophin receptors in prostate carcinoma.

Rationale: Neurotrophine tyrosine kinase receptors (NTR) are expressed in prostate carcinoma (PCa), and their distribution seems to be related to disease malignancy.

Material And Methods: In this article we analyzed the expression of NTRK1 (TrkA), NTRK2 (TrkB), NTRK3 (TrkC), and p75NTR in a 102 patient cohort with clinically localized tumors, which had been surgically treated with radical prostatectomy (RP). Among these, 61 patients received RP as sole treatment, and 41 patients received neoadjuvant hormone therapy (NHT) for 120 days with bicalutamide 150 mg/day.

Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro.

In the prostate, cellular growth and differentiation are finely regulated by a complex interaction between stromal and epithelial cells under the control of both autocrine and paracrine regulatory factors such as the nerve growth factor (NGF). However, the role of NGF and its receptors including the high-affinity p-140 TrkA and the low-affinity p75 NTR receptors remains controversial. Moreover prostate tissues stored other neutrophins such as NT3, NT4 and brain derived neutrophic factor (BDNF) as well as the corresponding receptors (NTRs).

Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells.

During its biological progression, prostate cancer frequently develops dependence on growth factor receptors and their downstream signalling messengers, including c-Src. Evidence for this supports the choice of c-Src as a therapeutic target in the prevention of tumour spreading. Two new pyrazolo[3,4-d]pyrimidines c-Src inhibitors, SI35 and SI40, were used to investigate the role of c-Src in the control of the aggressive phenotype of prostate carcinoma cell line, PC3.

Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice.

The activation of epidermal growth factor receptor (EGF-R) plays a key role in the promotion of proliferation and invasion in prostatic carcinoma (PCa). Gefitinib (Iressa; ZD1839), an orally active EGF-R tyrosine kinase inhibitor, has shown an important anti-proliferative activity in tumors expressing EGF-R both in vitro and in vivo. Our aim was to elucidate the role of gefitinib in the modulation of the metastatic spread of PCa cells.

Role of nitric oxide in the impairment of circular muscle contractility of distended, uninflamed mid-colon in TNBS-induced acute distal colitis in rats.

Aim: To evaluate the role of nitric oxide (NO) in the motor disorders of the dilated uninflamed mid-colon (DUMC) from trinitrobenzene sulfonic acid (TNBS)-induced acute distal colitis in rats.

Methods: Colitis was induced in male Sprague-Dawley rats by a single intracolonic administration of TNBS. Control rats received an enema of 0.

Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity. EGF-receptor inhibition may prevent tumor cell dissemination.

Urokinase-type plasminogen activator receptor (uPAR) and Epidermal Growth Factor Receptor (EGFR) are ubiquitous receptors involved in the control of a variety of cellular processes frequently found altered in cancer cells. The EGFR has been recently described to play a transduction role of uPAR stimuli, mediating uPA-induced proliferation in highly malignant cells that overexpress uPAR. We compared the uPA production, the presence of uPAR, AR, EGFR and Her2 with the chemotaxis and the Matrigel invasion in ten human PCa cell lines and observed that: (1) the levels of Her2, but not of EGFR, as well as the uPA secretion, cell motility and Matrigel invasion were statistically higher in AR negative than in AR positive PCa cells; (2) the uPA secretion and uPA Rexpression were positively related to Matrigel invasion; (3) the EGF was able to stimulate chemotaxis and Matrigel invasion in a dose-dependent manner; (4) the EGF-induced cell migration was statistically higher inAR negative than in AR positive cells with a similar increase with respect to basal value (about 2.

Epithelial and prostatic marker expression in short-term primary cultures of human prostate tissue samples.

Despite the high incidence and mortality of prostate cancer (PCa), molecular and genetic events involved in its progression remain poorly understood due to difficulty in establishing premalignant lesions and primary tumors in vitro. The most used cancer cell lines, which have been established primarily from metastatic lesions, do not accurately recapitulate the biological behaviour of primary tumors as compared to primary cultures generated from clinical PCa specimens. However, prostate primary cultures contain a mixture of different cell types which must be characterized completely to obtain reproducible information for studying the biology of single tumors and for evaluating the effectiveness of therapeutical approaches.

Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro.

Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines.