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Increased consumption of fruits and vegetables can represent an easy strategy to significantly reduce the incidence of cancer. From this observation, derived mostly from epidemiological data, the new field of chemoprevention has emerged in the primary and secondary prevention of cancer. Chemoprevention is defined as the use of natural or synthetic compounds able to stop, reverse, or delay the process of tumorigenesis in its early stages. A large number of phytochemicals are potentially capable of simultaneously inhibiting and modulating several key factors regulating cell proliferation in cancer cells. Quercetin is a flavonoid possessing potential chemopreventive properties. It is a functionally pleiotropic molecule, possessing multiple intracellular targets, affecting different cell signaling processes usually altered in cancer cells, with limited toxicity on normal cells. Simultaneously targeting multiple pathways may help to kill malignant cells and slow down the onset of drug resistance. Among the different substrates triggered by quercetin, we have reviewed the ability of the molecule to inhibit protein kinases involved in deregulated cell growth in cancer cells.

The first aim of the present study is the development of a new ruthenium(III) complex, belonging to NAMI-A class, with a potentially high cytotoxic ability. The presence of a fully protected sugar moiety as ruthenium ligand should increase the complex ability to cross cellular membranes. Furthermore, it sets this molecule in the area of biocompatible agents as tumor drug. The second, more relevant, purpose is to verify the ruthenium complexes activity after loading into liposomes. We reported the characterization and in vitro biological assays of pyridine derivatives of ruthenium complexes loaded into Egg l -α-phosphatidylcholine cholesterol/DSPE-PEG liposomes. Dynamic light scattering estimates that the sizes of all obtained liposomes are in the 100 nm range. This value is suitable for in vivo use. The loading ability and release kinetic allowed selecting the best ratio between the lipid fraction and metal to be tested in cellular experiments. The growth inhibitory effects of both liposomal and free complex in PC-3 prostate cancer cell lines demonstrate a high cytotoxic ability of the liposome entrapped ruthenium (III) complex suggesting additional role further the antimetastatic function.

Four 4-nitrophenyl-functionalized benzofuran (BF1, BF2) and benzodifuran (BDF1, BDF2) compounds were synthesized by a convenient route based on the Craven reaction. All the compounds underwent a detailed chemical physical characterization to evaluate their structural, thermal and optical properties. An investigation on the therapeutic potential of the reported compounds was performed by analyzing their antiproliferative activity on prostatic tumour cells (PC-3). In both classes of compounds, anticancer potential is in direct correlation with the lipophilicity. From our study it emerged that antiproliferative activity was higher for benzofuran derivatives as compared to benzodifuran systems. Moreover, we report a mechanistic study relative to the most promising molecule, i.e. the apolar benzofuran BF1, that relates the antiproliferative properties found in our investigation to its ability to bind telomeric DNA (proven by CD and fluorescence techniques on tel(22) G4 DNA), and highlights its unexpected impact on cell cycle progression. (C) 2018 Elsevier B.V. All rights reserved.

The lipid phosphatase Ship2 represents a drug discovery target for the treatment of different diseases, including cancer. Its C-terminal sterile alpha motif domain (Ship2-Sam) associates with the Sam domain from the EphA2 receptor (EphA2-Sam). This interaction is expected to mainly induce pro-oncogenic effects in cells therefore, inhibition of the Ship2-Sam/EphA2-Sam complex may represent an innovative route to discover anti-cancer therapeutics. In the present work, we designed and analyzed several peptide sequences encompassing the interaction interface of EphA2-Sam for Ship2-Sam. Peptide conformational analyses and interaction assays with Ship2-Sam conducted through diverse techniques (CD, NMR, SPR and MST), identified a positively charged penta-amino acid native motif in EphA2-Sam, that once repeated three times in tandem, binds Ship2-Sam. NMR experiments show that the peptide targets the negatively charged binding site of Ship2-Sam for EphA2-Sam. Preliminary in vitro cell-based assays indicate that -at 50 µM concentration- it induces necrosis of PC-3 prostate cancer cells with more cytotoxic effect on cancer cells than on normal dermal fibroblasts. This work represents a pioneering study that opens further opportunities for the development of inhibitors of the Ship2-Sam/EphA2-Sam complex for therapeutic applications.

Herein, we present a spectroscopic (CD and UV) and SEM study of a phenylalanine derivative carrying a terminal alkyne moiety and indicated by us CF3IIIPhe, with particular attention to its interaction with Cu(II) cation and some biological macromolecules, as well as a preliminary evaluation of its effect on cancerous cells. CD spectroscopy evidenced the ability of CF3IIIPhe to interact with tel26 and c-myc, two quadruplex DNA (G4 DNA) models explored in this study. Other CD and UV studies revealed the ability of the unnatural amino acid to form aggregates in aqueous solution, to bind Cu(II) cation, and to interact with bovine serum albumin (BSA). Cellular studies demonstrated CF3IIIPhe antiproliferative activity on PC3 cells. Its ability to bind telomeric DNA was verified with tel26 by CD investigation and SEM analysis, that revealed a noteworthy change in DNA morphology (mainly based on nanosphere structures) by CF3IIIPhe, confirming its G4-DNA binding ability already evidenced by spectroscopy.

The success of platinum complexes as chemiotherapeutic drugs pushed the scientific community to design new transition metal based complexes. to fight cancer and overcome the severe side effects and the insurgence of platinum resistance [1]..Among these compound ruthenium (III) complexes have been demonstrated very powerful against metastatic tumour but very poor is their action as cytotoxic agent.[2] The first aim of the present study was the development of a new ruthenium(III) complex, belonging to NAMI-A class, bearing to pyridine ligand a fully protected sugar moiety (RuPyTri). The presence of carbohydrate in coordination sphere should increase the complex ability to cross cellular membranes and sets this molecule in the area of biocompatible agents as tumour drug. The stability of the complex was studied and compared to RuPy complex in solution at different pH following UV-VIS spectra. The second, more relevant, purpose was to verify the ruthenium complexes activity after loading into liposomes. Liposomes can induce different mechanisms of delivery, increase the ability to cross cell membrane and stabilize the complexes reducing the water exchange. The lipid composition Egg L-α-phosphatidylcholine cholesterol / DSPE-PEG liposomes was selected to reproduce analog supramolecular aggregates in clinical use to vehicle doxorubicin (Doxil). Ruthenium complexes were loaded into liposomes using the passive equilibration loading method estimating the entrapped metal amount by ICP-MS. Full drug containing liposomes were structurally characterized by dynamic light scattering (DLS). Measurements confirm that sizes of all liposomes are in the 100 nm range, suitable for in vivo use. Loading ability and release kinetic allowed to select the best ratio between the lipid fraction and the metal to be tested in cellular experiments. Stability and drug release properties of ruthenium containing liposomes were confirmed in buffer. The growth inhibitory effects of both liposomal and free complex in PC3 prostate cancer cell lines validate a high cytotoxic ability of the liposome entrapped ruthenium (III) complexes.

Nodal is a potent embryonic morphogen belonging to the TGF-beta superfamily. Typically, it also binds to the ALK4/ActRIIB receptor complex in the presence of the co-receptor Cripto-1. Nodal expression is physiologically restricted to embryonic tissues and human embryonic stem cells, is absent in normal cells but re-emerges in several human cancers, including melanoma, breast, and colon cancer. Our aim was to obtain mAbs able to recognize Nodal on a major CBR (Cripto-Binding-Region) site and to block the Cripto-1-mediated signalling. To achieve this, antibodies were raised against hNodal(44-67) and mAbs generated by the hybridoma technology. We have selected one mAb, named 3D1, which strongly associates with full-length rhNodal (KD 1.4 nM) and recognizes the endogenous protein in a panel of human melanoma cell lines by western blot and FACS analyses. 3D1 inhibits the Nodal-Cripto-1 binding and blocks Smad2/3 phosphorylation. Data suggest that inhibition of the Nodal-Cripto-1 axis is a valid therapeutic approach against melanoma and 3D1 is a promising and interesting agent for blocking Nodal-Cripto mediated tumor development. These findings increase the interest for Nodal as both a diagnostic and prognostic marker and as a potential new target for therapeutic intervention.

A series of neutral and cationic gold(I) complexes bearing a glucopyranoside-incorporated N-heterocyclic carbene (NHC) ligand are synthetized and structurally characterized. Different secondary ligands (chlorido, phosphane, or sugar–NHC) are employed to tune the properties of the complexes. The antiproliferative effects of the compounds are evaluated against PC-3 prostate cancer cells and a panel of human tumor cell lines. The activities of the phosphane complexes are comparable to that observed for cisplatin. The combined results provide further insights into the biological behavior of NHC–gold complexes.