Publications by authors named "Alessandro Di Domizio"

9 Publications

  • Page 1 of 1

Three-Dimensional Proteome-Wide Scale Screening for the 5-Alpha Reductase Inhibitor Finasteride: Identification of a Novel Off-Target.

J Med Chem 2021 04 12;64(8):4553-4566. Epub 2021 Apr 12.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy.

Finasteride, a 5-alpha reductase (5α-R) inhibitor, is a widely used drug for treating androgen-dependent conditions. However, its use is associated with sexual, psychological, and physical complaints, suggesting that other mechanisms, in addition to 5α-R inhibition, may be involved. Here, a multidisciplinary approach has been used to identify potential finasteride off-target proteins. SPILLO-PBSS software suggests an additional inhibitory activity of finasteride on phenylethanolamine -methyltransferase (PNMT), the limiting enzyme in formation of the stress hormone epinephrine. The interaction of finasteride with PNMT was supported by docking and molecular dynamics analysis and by assay, confirming the inhibitory nature of the binding. Finally, this inhibition was also confirmed in an rat model. Literature data indicate that PNMT activity perturbation may be correlated with sexual and psychological side effects. Therefore, results here obtained suggest that the binding of finasteride to PNMT might have a role in producing the side effects exerted by finasteride treatment.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154553PMC
April 2021

Natural Compounds in Prostate Cancer Prevention and Treatment: Mechanisms of Action and Molecular Targets.

Cells 2020 02 18;9(2). Epub 2020 Feb 18.

Department of Pharmacological and Biomolecular Sciences, University of Milano, 20122 Milano, Italy.

Prostate cancer (PCa) represents a major cause of cancer mortality among men in developed countries. Patients with recurrent disease initially respond to androgen-deprivation therapy, but the tumor eventually progresses into castration-resistant PCa; in this condition, tumor cells acquire the ability to escape cell death and develop resistance to current therapies. Thus, new therapeutic approaches for PCa management are urgently needed. In this setting, natural products have been extensively studied for their anti-PCa activities, such as tumor growth suppression, cell death induction, and inhibition of metastasis and angiogenesis. Additionally, numerous studies have shown that phytochemicals can specifically target the androgen receptor (AR) signaling, as well as the PCa stem cells (PCSCs). Interestingly, many clinical trials have been conducted to test the efficacy of nutraceuticals in human subjects, and they have partially confirmed the promising results obtained in vitro and in preclinical models. This article summarizes the anti-cancer mechanisms and therapeutic potentials of different natural compounds in the context of PCa prevention and treatment.
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http://dx.doi.org/10.3390/cells9020460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072821PMC
February 2020

3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line.

Bioorg Med Chem 2020 02 30;28(4):115300. Epub 2019 Dec 30.

School of Medicine and Surgery, Experimental Neurology Unit and Milan Center for Neuroscience, University of Milano-Bicocca, via Cadore 48, 20900 Monza, MB, Italy.

The imidazobenzoxazin-5-thione MV1035, synthesized as a new sodium channel blocker, has been tested on tumoral cells that differ for origin and for expressed Na pool (U87-MG, H460 and A549). In this paper we focus on the effect of MV1035 in reducing U87 glioblastoma cell line migration and invasiveness. Since the effect of this compound on U87-MG cells seemed not dependent on its sodium channel blocking capability, alternative off-target interaction for MV1035 have been identified using SPILLO-PBSS software. This software performs a structure-based in silico screening on a proteome-wide scale, that allows to identify off-target interactions. Among the top-ranked off-targets of MV1035, we focused on the RNA demethylase ALKBH5 enzyme, known for playing a key role in cancer. In order to prove the effect of MV1035 on ALKBH5 in vitro coincubation of MV1035 and ALKBH5 has been performed demonstrating a consequent increase of N6-methyladenosine (m6A) RNA. To further validate the pathway involving ALKBH5 inhibition by MV1035 in U87-MG reduced migration and invasiveness, we evaluated CD73 as possible downstream protein. CD73 is an extrinsic protein involved in the generation of adenosine and is overexpressed in several tumors including glioblastoma. We have demonstrated that treating U87-MG with MV1035, CD73 protein expression was reduced without altering CD73 transcription. Our results show that MV1035 is able to significantly reduce U87 cell line migration and invasiveness inhibiting ALKBH5, an RNA demethylase that can be considered an interesting target in fighting glioblastoma aggressiveness. Our data encourage to further investigate the MV1035 inhibitory effect on glioblastoma.
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http://dx.doi.org/10.1016/j.bmc.2019.115300DOI Listing
February 2020

The emerging role of paraptosis in tumor cell biology: Perspectives for cancer prevention and therapy with natural compounds.

Biochim Biophys Acta Rev Cancer 2020 04 3;1873(2):188338. Epub 2020 Jan 3.

Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy. Electronic address:

Standard anti-cancer therapies promote tumor growth suppression mainly via induction of apoptosis. However, in most cases cancer cells acquire the ability to escape apoptotic cell death, thus becoming resistant to current treatments. In this setting, the interest in alternative cell death modes has recently increased. Paraptosis is a new form of programmed cell death displaying endoplasmic reticulum (ER) and/or mitochondria dilation, generally due to proteostasis disruption or redox and ion homeostasis alteration. Recent studies have highlighted that several natural compounds can trigger paraptosis in different tumor cell lines. Here, we review the molecular mechanisms underlying paraptotic cell death, as well as the natural products inducing this kind of cell death program. A better understanding of paraptosis should facilitate the development of new therapeutic strategies for cancer prevention and treatment.
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http://dx.doi.org/10.1016/j.bbcan.2020.188338DOI Listing
April 2020

Unraveling the molecular mechanisms and the potential chemopreventive/therapeutic properties of natural compounds in melanoma.

Semin Cancer Biol 2019 12 22;59:266-282. Epub 2019 Jun 22.

Department of Pharmacological and Biomolecular Sciences, University of Milano, Milano, Italy. Electronic address:

Melanoma is the most fatal form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, targeted therapy and immunotherapy. However, these treatment strategies are associated with development of drug resistance and severe side effects. In recent years, natural compounds have also been extensively studied for their anti-melanoma effects, including tumor growth inhibition, apoptosis induction, angiogenesis and metastasis suppression and cancer stem cell elimination. Moreover, a considerable number of studies reported the synergistic activity of phytochemicals and standard anti-melanoma agents, as well as the enhanced effectiveness of their synthetic derivatives and novel formulations. However, clinical data confirming these promising effects in patients are still scanty. This review emphasizes the anti-tumor mechanisms and potential application of the most studied natural products for melanoma prevention and treatment.
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http://dx.doi.org/10.1016/j.semcancer.2019.06.011DOI Listing
December 2019

SPILLO-PBSS: detecting hidden binding sites within protein 3D-structures through a flexible structure-based approach.

J Comput Chem 2014 Oct 1;35(27):2005-17. Epub 2014 Sep 1.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126, Milan, Italy; Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli, 25, 20133, Milan, Italy.

The study reports a flexible structure-based approach aimed at identifying binding sites within target proteins starting from a well-defined reference binding site. The method, named SPILLO potential binding sites searcher (SPILLO-PBSS), includes a suitably designed tolerance which allows an efficient recognition of the potential binding sites regardless of both involved residues and protein conformation. Hence, the proposed method overcomes the rigidity which affects the available approaches and which prevents a proper analysis of distorted binding sites. We apply SPILLO-PBSS to several test cases, including the search for the guanosine diphosphate binding site in distorted H-Ras proteins and the identification of acetylcholine binding proteins from among a library of heterogeneous resolved proteins. Tests are also performed to compare SPILLO-PBSS with other related and available methods. The encouraging results confirm the notable potentialities of this approach and lay the foundation for its use to analyze and predict target proteins on a proteome-wide scale.
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http://dx.doi.org/10.1002/jcc.23714DOI Listing
October 2014

Sugar-based inhibitors of Ras activation: biological activity and identification of Ras-inhibitor binding interface.

Enzymes 2013 8;33 Pt A:95-116. Epub 2013 Aug 8.

Department of Biotechnology and Biosciences, University of Milano Bicocca, Milano, Italy. Electronic address:

Inhibition of oncogenic Ras activation through small molecules is a promising approach to the pharmacologic treatment of human tumors. A common strategy to block Ras activation and signal transduction is based on molecules that interfere with the guanine exchange factors (GEF)-promoted nucleotide exchange. We developed several generations of small molecules active in inhibiting Ras activation at low micromolar concentrations. Some of these compounds are more active on cell lines expressing oncogenic Ras than on normal cells and are therefore good hit compounds for anticancer drug development. The molecules belonging to the last generation are soluble in water and allowed the identification of binding site on Ras by means of NMR experiments in deuterated water. The experimentally-determined Ras-binding site comprises residues belonging to the α-2 helix and the β-3 strand of the central β-sheet in the Switch 2 region. Synthetic molecules bind Ras in a region belonging to the more extended Ras/GEF-binding site, and a possible mechanism of Ras inhibition by these compounds can be the blockade of GEF-mediated nucleotide exchange.
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http://dx.doi.org/10.1016/B978-0-12-416749-0.00005-1DOI Listing
August 2014

Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-Ras(G13D).

Biochem Biophys Res Commun 2009 Sep 18;386(4):593-7. Epub 2009 Jun 18.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 20126 Milan, Italy.

Mutation of RAS genes is a critical event in the pathogenesis of different human tumors and in some developmental disorders. Here we present an arabinose-derived bicyclic compound displaying selective cytotoxicity in human colorectal cancer cells expressing K-Ras(G13D), that shows high intrinsic nucleotide exchange rate. We characterize binding of bicyclic compounds by docking and NMR experiments and their inhibitory activity on GEF-mediated nucleotide exchange on wild-type and mutant Ras proteins. We demonstrate that the in vitro inhibition of Ras nucleotide exchange depends on the molar ratio between Ras and its GEF activator, suggesting that the observed in vivo selective effect may depend on biochemical parameters and actual intracellular concentration of the Ras protein and its regulators.
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http://dx.doi.org/10.1016/j.bbrc.2009.06.069DOI Listing
September 2009

First experimental identification of Ras-inhibitor binding interface using a water-soluble Ras ligand.

Bioorg Med Chem Lett 2009 Aug 30;19(15):4217-22. Epub 2009 May 30.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy.

By combining in the same molecule Ras-interacting aromatic moieties and a sugar, we prepared a water-soluble Ras ligand that binds Ras and inhibits guanine nucleotide exchange. With this compound it was possible to determine experimentally by a (15)N-edited HSQC NMR experiment the ligand-Ras binding interface.
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http://dx.doi.org/10.1016/j.bmcl.2009.05.107DOI Listing
August 2009
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