Adriano Angelucci

Università degli Studi dell'Aquila, Aquila, Abruzzo, Italy

Are you Adriano Angelucci?

Claim your profile

Publications (108)274.81 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.
    Journal of Medicinal Chemistry 12/2014; · 5.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The protein kinase Src is frequently over-activated in advanced cancers where it modulates the signaling transduction cascade of several growth factors. The feasibility of combination treatment of Src inhibitors with chemotherapy is currently under investigation. We evaluated the anti-tumoral effect of paclitaxel (PTX) in combination with S13, a tyrosine kinase inhibitor with a prevalent specificity for Src, in a hormone-insensible prostate cancer (PCa) cell model. In vivo, combination treatment with PTX and S13 reduced dramatically PCa tumor growth with a relevant difference in the density of new blood vessels with respect to control and single treatments. This reduction was determined by a concomitant impairment of endothelial cell migration and of VEGF release by cancer cells. In fact, S13, when used alone, was sufficient to reduce tubule formation in vivo, and to inhibit VEGFR2 activation and FAK expression in endothelial cells. In addition, the combination treatment determined a significant reduction in ROS production and HIF1 stabilization in PCa cells respect to single treatments with S13 or PTX. In conclusion, Src-inhibition could be an effective therapeutic strategy aimed at supporting the anti-angiogenic action of PTX in aggressive PCa.
    Experimental Cell Research 08/2014; · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metastatic occurrence is the principal cause of death in breast cancer patients. The high osteotropism makes breast cancer the most common primary tumor type associated with metastatic bone disease. The peculiar clinical aspects associated with metastases limited to the skeletal system suggest considering these cases as a distinctive subset of metastatic patients with a better prognosis. Because bone is frequently the first metastatic site in disease relapse, it is feasible that the next improvement in therapeutic options for bone metastatic disease could be associated with an improvement of survival expectation and quality of life in breast cancer patients. Study of the molecular basis of bone remodeling and breast cancer osteotropism has allowed identification of several therapeutic candidates involved in formation and progression of bone metastases. These targets are frequently the determinants of positive feedback between the tumor and bone cells whose clinical outcome is osteolytic lesions. In this review, we discuss the physiopathologic features underlying targeted therapeutic strategies aimed at interfering with the aberrant bone remodeling associated with breast cancer metastases.
    World journal of clinical oncology. 08/2014; 5(3):335-347.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism. Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression. Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive correlation between stromal MCT4 and tumor MCT1 expression. Our data demonstrated that PCa progression may benefit of MCT1 expression in tumor cells and of MCT4 in tumor-associated stromal cells. Therefore, MCTs may result promising therapeutic targets in different phases of neoplastic transformation according to a strategy aimed to contrast the energy metabolic adaptation of PCa cells to stressful environments.
    BMC Cancer 03/2014; 14(1):154. · 3.32 Impact Factor
  • Source
    Nadia Rucci, Adriano Angelucci
    [Show abstract] [Hide abstract]
    ABSTRACT: The onset of metastases dramatically changes the prognosis of prostate cancer patients, determining increased morbidity and a drastic fall in survival expectancy. Bone is a common site of metastases in few types of cancer, and it represents the most frequent metastatic site in prostate cancer. Of note, the prevalence of tumor relapse to the bone appears to be increasing over the years, likely due to a longer overall survival of prostate cancer patients. Bone tropism represents an intriguing challenge for researchers also because the preference of prostate cancer cells for the bone is the result of a sequential series of targetable molecular events. Many factors have been associated with the peculiar ability of prostate cancer cells to migrate in bone marrow and to determine mixed osteoblastic/osteolytic lesions. As anticipated by the success of current targeted therapy aimed to block bone resorption, a better understanding of molecular affinity between prostate cancer and bone microenvironment will permit us to cure bone metastasis and to improve prognosis of prostate cancer patients.
    BioMed Research International 01/2014; 2014:167035. · 2.71 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. However molecular mechanisms underlying VPA action in PCa cells are largely unknown and further experimental validation to prove its potential application in clinic practice is needed.RESULTSIn our study we show that VPA is a potent inducer of neuro-endocrine transdifferentiation (NET) in androgen receptor null PCa cells, both in vitro and in vivo. NET was an early event detectable through the expression of neuro-endocrine (NE) markers within 72 hr after VPA treatment and it was associated to a reduction in the overall cell proliferation. When we interrupted VPA treatment we observed the recovery in residual cells of the basal proliferation rate both in vitro and in a xenograft model. The NET process was related to Bcl-2 over-expression in non-NE PCa cells and to the activation of PPARγ in NE cells. The use of specific PPARγ antagonist was able to reduce significantly the expression of NE markers induced by VPA.CONCLUSIONS Our data indicate that the use of VPA as monotherapy in PCa has to be considered with extreme caution, since it may induce an unfavorable NET. In order to counteract the VPA-induced NET, the inhibition of PPARγ may represent a suitable adjuvant treatment strategy and awaits further experimental validation. Prostate 68: 588–598, 2008. © 2008 Wiley-Liss, Inc.
  • Source
  • Source
    Psychiatry and Clinical Neurosciences 07/2013; 67(5):363-4. · 2.04 Impact Factor
  • Psychiatry and Clinical Neurosciences 07/2013; 67:363-364. · 1.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Starting from our in-house library of pyrazolo[3,4-d]pyrimidines, cross-docking simulation was conducted on Bcr-Abl T315I mutant to select new derivatives for biological investigations. Among the selected compounds (2a-e), derivative 2b showed a high activity against the Bcr-Abl T315I mutant (Ki = 36 nM). Binding free energy calculation (MM-GBSA), molecular interaction field (MIF) analysis and free energy perturbation (FEP) studies highlighted the importance of a bromine atom of the para position of the N1 side chain phenyl ring for the interaction with the hydrophobic region I in the T315I mutant. A series of 4-bromo derivatives was thus synthesized and biologically evaluated in cell-free assays (c-Src, Abl wt, Abl T315I mutant) and in the murine myeloid 32D cell lines expressing the human wild type p210-Bcr-Abl or the Bcr-Abl T315I mutant. Compound 2j was identified as the most promising derivative showing a good balance of different ADME properties, high activity in cell-free assays and an interesting sub-micromolar potency against T315I Bcr-Abl expressing cells. In addition, liposome encapsulated 2j was tested on 32D-p210 and 32D-T315I cell lines at concentrations of 0.1 and 1 μM in comparison with the DMSO dissolved 2j. Liposomal formulation increases the solubility of pyrazolo[3,4-d]pyrimidines preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated for 17 days with 2j showed a more than 50% reduction in tumor volumes when compared to placebo treated mice.
    Journal of Medicinal Chemistry 06/2013; · 5.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Design and synthesis of prodrugs of promising drug candidates represents a valid strategy to overcome the lack of favorable ADME properties, in particular aqueous solubility and bioavailability. We report herein the successful application of this strategy with two representative pyrazolo[3,4-d]pyrimidine derivatives (1 and 2), which led to the development of the corresponding and highly water-soluble antitumor prodrugs (7 and 8). In vitro studies confirmed a significant improvement of aqueous solubility and, for compound 8, good plasma stability, suggesting superior in vivo bioavailability. As expected, the uncleaved water-soluble prodrugs 7 and 8 showed no activity toward the enzymatic targets (c-Src and c-Abl) but revealed promising antiproliferative activity in myeloid cell lines, as a consequence of the in vitro hydrolysis of the selected solubilizing moiety, followed by the release of the active compounds (1 and 2).
    ACS Medicinal Chemistry Letters 05/2013; · 3.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Based on the growing deal of data concerning the biological activity of flavonoid-rich natural products, the aim of the present study was to explore in vitro the potential anti-tumoral activity of Citrus Bergamia (bergamot) juice (BJ), determining its molecular interaction with cancer cells. Here we show that BJ reduced growth rate of different cancer cell lines, with the maximal growth inhibition observed in neuroblastoma cells (SH-SY5Y) after 72 hs of exposure to 5% BJ. The SH-SY5Y antiproliferative effect elicited by BJ was not due to a cytotoxic action and it did not induce apoptosis. Instead, BJ stimulated the arrest in the G1 phase of cell cycle and determined a modification in cellular morphology, causing a marked increase of detached cells. The inhibition of adhesive capacity on different physiologic substrates and on endothelial cells monolayer were correlated with an impairment of actin filaments, a reduction in the expression of the active form of focal adhesion kinase (FAK) that in turn caused inhibition of cell migration. In parallel, BJ seemed to hinder the association between the neural cell adhesion molecule (NCAM) and FAK. Our data suggest a mechanisms through which BJ can inhibit important molecular pathways related to cancer-associated aggressive phenotype and offer new suggestions for further studies on the role of BJ in cancer treatment.
    PLoS ONE 04/2013; 8(4):e61484. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: (hbd) PRELP is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein Proline/aRginine-rich End Leucine-rich repeat Protein (PRELP). (hbd) PRELP inhibits osteoclastogenesis entering pre-fusion osteoclasts through a chondroitin sulfate- and annexin 2-dependent mechanism and reducing the nuclear factor-κB transcription factor activity. In this work we hypothesized that (hbd) PRELP could have a pharmacological relevance counteracting bone loss in a variety of in vivo models of bone diseases induced by exacerbated osteoclast activity. In healthy mice, we demonstrated that the peptide targeted the bone and increased trabecular bone mass over basal level. In mice treated with retinoic acid to induce an acute increase of osteoclast formation, the peptide consistently antagonized osteoclastogenesis and prevented the increase of the serum levels of the osteoclast-specific marker tartrate-resistant acid phosphatase. In ovariectomized mice, in which osteoclast activity was chronically enhanced by estrogen deficiency, (hbd) PRELP counteracted exacerbated osteoclast activity and bone loss. In mice carrying osteolytic bone metastases, in which osteoclastogenesis and bone resorption were enhanced by tumor cell derived factors, (hbd) PRELP reduced the incidence of osteolytic lesions, both preventively and curatively, with mechanisms involving impaired tumor cell homing to bone and tumor growth in the bone microenvironment. Interestingly, in tumor-bearing mice, (hbd) PRELP also inhibited breast tumor growth in orthotopic sites and development of metastatic disease in visceral organs, reducing cachexia and improving survival especially when administered preventively. (hbd) PRELP was retained in the tumor tissue and appeared to affect tumor growth by interacting with the microenvironment rather than by directly affecting the tumor cells. Since safety studies and high dose treatments revealed no adverse effects, (hbd) PRELP could be employed as novel biological agent to combat experimentally induced bone loss and breast cancer metastases, with a potential translational impact. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2013; · 6.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pim-1 is a serine/threonine kinase critically involved in the initiation and progression of various types of cancer, especially leukemia, lymphomas and solid tumors such as prostate, pancreas and colon, and is considered a potential drug target against these malignancies. In an effort to discover new potent Pim-1 inhibitors, a previously identified ATP-competitive indolyl-pyrrolone scaffold was expanded to derive structure-activity relationship data. A virtual screening campaign was also performed, which led to the discovery of additional ATP-competitive inhibitors as well as a series of 2-aminothiazole derivatives, which are noncompetitive with respect to both ATP and peptide substrate. This mechanism of action, which resembles allosteric inhibition, has not previously been characterized for Pim-1. Notably, further evaluation of the 2-aminothiazoles indicated a synergistic inhibitory effect in enzymatic assays when tested in combination with ATP-competitive inhibitors. A synergistic effect in the inhibition of cell proliferation by ATP-competitive and ATP-noncompetitive compounds was also observed in prostate cancer cell lines (PC3), where all Pim-1 inhibitors tested in showed synergism with the known anticancer agent, paclitaxel. These results further establish Pim-1 as a target in cancer therapy, and highlight the potential of these agents for use as adjuvant agents in the treatment of cancer diseases in which Pim-1 is associated with chemotherapeutic resistance.
    ChemMedChem 03/2013; 8(3):484-96. · 3.05 Impact Factor
  • ANTICANCER RESEARCH; 01/2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prostate is the most frequent site of cancer in men aged 68 years and older. Although prostate cancer is frequently a slow-progressing cancer, the increase in lifespan is posing new challenges in order to avoid prostate cancer-associated mortality. epidemiological studies have clearly demonstrated that the westernised lifestyle and diet may fuel prostate cancer incidence and mortality, and the associated current pandemic of obesity is becoming one of the principal risk factors for age-related chronic diseases. obesity and ageing seem to contribute independently to deregulating adipose tissue homoeostasis and in turn systemic metabolism. nowadays, adipose tissue is recognised as an active and complex endocrine and immunological organ able to control the homoeostasis of different distant organs through the release of a variety of factors, collectively termed adipokines. These factors are master regulators of energy balance and immune response and may account for some of the most frequent obesity- and age-related health problems, including cancer. The dissection of mechanisms leading to altered metabolic control by adipose tissue will eventually indicate a new preventive strategy for prostate cancer.
    Oncology & Hematology Review. 01/2013; 9(1):10-15.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The formation of new blood vessels is an essential therapeutic target in many diseases such as cancer, ischemic diseases, and chronic inflammation. In this regard, extremely low-frequency (ELF) electromagnetic fields (EMFs) seem able to inhibit vessel growth when used in a specific window of amplitude. To investigate the mechanism of anti-angiogenic action of ELF-EMFs we tested the effect of a sinusoidal magnetic field (MF) of 2 mT intensity and frequency of 50 Hz on endothelial cell models HUVEC and MS-1 measuring cell status and proliferation, motility and tubule formation ability. MS-1 cells when injected in mice determined a rapid tumor-like growth that was significantly reduced in mice inoculated with MF-exposed cells. In particular, histological analysis of tumors derived from mice inoculated with MF-exposed MS-1 cells indicated a reduction of hemangioma size, of blood-filled spaces, and in hemorrhage. In parallel, in vitro proliferation of MS-1 treated with MF was significantly inhibited. We also found that the MF-exposure down-regulated the process of proliferation, migration and formation of tubule-like structures in HUVECs. Using western blotting and immunofluorescence analysis, we collected data about the possible influence of MF on the signalling pathway activated by the vascular endothelial growth factor (VEGF). In particular, MF exposure significantly reduced the expression and activation levels of VEGFR2, suggesting a direct or indirect influence of MF on VEGF receptors placed on cellular membrane. In conclusion MF reduced, in vitro and in vivo, the ability of endothelial cells to form new vessels, most probably affecting VEGF signal transduction pathway that was less responsive to activation. These findings could not only explain the mechanism of anti-angiogenic action exerted by MFs, but also promote the possible development of new therapeutic applications for treatment of those diseases where excessive angiogenesis is involved.
    PLoS ONE 01/2013; 8(11):e79309. · 3.53 Impact Factor
  • A. Angelucci, M. Bologna, P. Muzi, P.A. Properzi
    First Ed. - ISBN 978-88-506-5223-5 01/2013: pages 725-757; New Business Media - Edagricole - Sole 24ore.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone is the preferential site of distant metastasis in breast carcinoma (BrCa). Patients with metastasis restricted to bone (BO) usually show a longer overall survival compared to patients who rapidly develop multiple metastases also involving liver and lung. Hence, molecular predisposition to generate bone and visceral metastases (BV) represents a clear indication of poor clinical outcome. We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from BO and BV patients. The unsupervised hierarchical clustering of the resulting transcriptomes correlated with the clinical progression, segregating the BO from the BV profiles. Matching the twofold significantly regulated genes from Affymetrix and Agilent chips resulted in a 15-gene signature with 13 upregulated and two downregulated genes in BV versus BO bone metastasis samples. In order to validate the resulting signature, we isolated different MDA-MB-231 clonal subpopulations that metastasize only in the bone (MDA-BO) or in bone and visceral tissues (MDA-BV). Six of the signature genes were also significantly upregulated in MDA-BV compared to MDA-BO clones. A group of upregulated genes, including Hemoglobin B (HBB), were involved in oxygen metabolism, and in vitro functional analysis of HBB revealed that its expression in the MDA subpopulations was associated with a reduced production of hydrogen peroxide. Expression of HBB was detected in primary BrCa tissue but not in normal breast epithelial cells. Metastatic lymph nodes were frequently more positive for HBB compared to the corresponding primary tumors, whereas BO metastases had a lower expression than BV metastases, suggesting a positive correlation between HBB and ability of bone metastasis to rapidly spread to other organs. We propose that HBB, along with other genes involved in oxygen metabolism, confers a more aggressive metastatic phenotype in BrCa cells disseminated to bone. © 2012 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2012; 27(11):2387-98. · 6.04 Impact Factor

Publication Stats

1k Citations
274.81 Total Impact Points

Institutions

  • 2000–2014
    • Università degli Studi dell'Aquila
      • • Department of Biotechnological and Applied Clinical Sciences
      • • Department of Experimental Medicine
      Aquila, Abruzzo, Italy
  • 2013
    • Sapienza University of Rome
      • Department of Drug Chemistry and Technologies
      Roma, Latium, Italy
  • 2007–2011
    • Università degli Studi di Siena
      • Department of Medicine, Surgery and Neuroscience
      Siena, Tuscany, Italy