107 results on '"Marzo T"'
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2. Anticancer effects against colorectal cancer models of chloro(triethylphosphine)gold(I) encapsulated in PLGA–PEG nanoparticles
- Author
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Menconi, A., Marzo, T., Massai, L., Pratesi, A., Severi, M., Petroni, G., Antonuzzo, L., Messori, L., Pillozzi, S., and Cirri, D.
- Subjects
Anticancer complexes ,Auranofin ,Colorectal cancer ,PLGA–PEG nanoparticles - Published
- 2021
3. Elective cancer surgery in COVID-19–Free surgical pathways during the SARS-cov-2 pandemic: An international, multicenter, comparative cohort study
- Author
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James C Glasbey, Dmitri Nepogodiev, Joana Ff Simoes, Omar Omar, Elizabeth Li, Mary L Venn, Mohammad Abou Chaar, Vita Capizzi, Daoud Chaudhry, Anant Desai, Jonathan G Edwards, Jonathan P Evans, Marco Fiore, Jose Flavio Videria, Samuel J Ford, Ian Ganyli, Ewen A Griffiths, Rohan R Gujjuri, Angelos G Kolias, Haytham Ma Kaafarani, Ana Minaya-Bravo, Siobhan C McKay, Helen M Mohan, Keith Roberts, Carlos San Miguel-Méndez, Peter Pockney, Richard Shaw, Neil J Smart, Grant D Stewart, Sudha Sundar, Raghavan Vidya, Aneel A Bhangu, James C Glasbey, Omar Omar, Aneel A Bhangu, Kwabena Siaw-Acheampong, Ruth A Benson, Edward Bywater, Daoud Chaudhry, Brett E Dawson, Jonathan P Evans, James C Glasbey, Rohan R Gujjuri, Emily Heritage, Conor S Jones, Sivesh K Kamarajah, Chetan Khatri, Rachel A Khaw, James M Keatley, Andrew Knight, Samuel Lawday, Elizabeth Li, Harvinder S Mann, Ella J Marson, Kenneth A McLean, Siobhan C McKay, Emily C Mills, Dmitri Nepogodiev, Gianluca Pellino, Maria Picciochi, Elliott H Taylor, Abhinav Tiwari, Joana Ff Simoes, Isobel M Trout, Mary L Venn, Richard Jw Wilkin, Aneel A Bhangu, James C Glasbey, Neil J Smart, Ana Minaya-Bravo, Jonathan P Evans, Gaetano Gallo, Susan Moug, Francesco Pata, Peter Pockney, Salomone Di Saverio, Abigail Vallance, Dale Vimalchandran, Ewen A Griffiths, Sivesh K Kamarajah, Richard Pt Evans, Philip Townend, Keith Roberts, Siobhan McKay, John Isaac, Sohei Satoi, John Edwards, Aman S Coonar, Adrian Marchbank, Edward J Caruana, Georgia R Layton, Akshay Patel, Alessandro Brunelli, Samuel Ford, Anant Desai, Alessandro Gronchi, Marco Fiore, Max Almond, Fabio Tirotta, Sinziana Dumitra, Angelos Kolias, Stephen J Price, Daniel M Fountain, Michael D Jenkinson, Peter Hutchinson, Hani J Marcus, Rory J Piper, Laura Lippa, Franco Servadei, Ignatius Esene, Christian Freyschlag, Iuri Neville, Gail Rosseau, Karl Schaller, Andreas K Demetriades, Faith Robertson, Alex Alamri, Richard Shaw, Andrew G Schache, Stuart C Winter, Michael Ho, Paul Nankivell, Juan Rey Biel, Martin Batstone, Ian Ganly, Raghavan Vidya, Alex Wilkins, Jagdeep K Singh, Dinesh Thekinkattil, Sudha Sundar, Christina Fotopoulou, Elaine Leung, Tabassum Khan, Luis Chiva, Jalid Sehouli, Anna Fagotti, Paul Cohen, Murat Gutelkin, Rahel Ghebre, Thomas Konney, Rene Pareja, Rob Bristow, Sean Dowdy, T S Shylasree, R Kottayasamy Seenivasagam, Joe Ng, Keiiji Fujiwara, Grant D Stewart, Benjamin Lamb, Krishna Narahari, Alan McNeill, Alexandra Colquhoun, John McGrath, Steve Bromage, Ravi Barod, Veeru Kasivisvanathan, Tobias Klatte, Joana Ff Simoes, Tom Ef Abbott, Sadi Abukhalaf, Michel Adamina, Adesoji O Ademuyiwa, Arnav Agarwal, Murat Akkulak, Ehab Alameer, Derek Alderson, Felix Alakaloko, Markus Albertsmeiers, Osaid Alser, Muhammad Alshaar, Sattar Alshryda, Alexis P Arnaud, Knut Magne Augestad, Faris Ayasra, José Azevedo, Brittany K Bankhead-Kendall, Emma Barlow, David Beard, Ruth A Benson, Ruth Blanco-Colino, Amanpreet Brar, Ana Minaya-Bravo, Kerry A Breen, Chris Bretherton, Igor Lima Buarque, Joshua Burke, Edward J Caruana, Mohammad Chaar, Sohini Chakrabortee, Peter Christensen, Daniel Cox, Moises Cukier, Miguel F Cunha, Giana H Davidson, Anant Desai, Salomone Di Saverio, Thomas M Drake, John G Edwards, Muhammed Elhadi, Sameh Emile, Shebani Farik, Marco Fiore, J Edward Fitzgerald, Samuel Ford, Tatiana Garmanova, Gaetano Gallo, Dhruv Ghosh, Gustavo Mendonça Ataíde Gomes, Gustavo Grecinos, Ewen A Griffiths, Madalegna GrÜndl, Constantine Halkias, Ewen M Harrison, Intisar Hisham, Peter J Hutchinson, Shelley Hwang, Arda Isik, Michael D Jenkinson, Pascal Jonker, Haytham Ma Kaafarani, Debby Keller, Angelos Kolias, Schelto Kruijff, Ismail Lawani, Hans Lederhuber, Sezai Leventoglu, Andrey Litvin, Andrew Loehrer, Markus W Löffler, Maria Aguilera Lorena, Maria Marta Modolo, Piotr Major, Janet Martin, Hassan N Mashbari, Dennis Mazingi, Symeon Metallidis, Ana Minaya-Bravo, Helen M Mohan, Rachel Moore, David Moszkowicz, Susan Moug, Joshua S Ng-Kamstra, Mayaba Maimbo, Ionut Negoi, Milagros Niquen, Faustin Ntirenganya, Maricarmen Olivos, Kacimi Oussama, Oumaima Outani, Marie Dione Parreno-Sacdalanm, Francesco Pata, Carlos Jose Perez Rivera, Thomas D Pinkney, Willemijn van der Plas, Peter Pockney, Ahmad Qureshi, Dejan Radenkovic, Antonio Ramos-De la Medina, Keith Roberts, April C Roslani, Martin Rutegård, Juan José Segura-Sampedro, Irène Santos, Sohei Satoi, Raza Sayyed, Andrew Schache, Andreas A Schnitzbauer, Justina O Seyi-Olajide, Neil Sharma, Richard Shaw, Sebastian Shu, Kjetil Soreide, Antonino Spinelli, Grant D Stewart, Malin Sund, Sudha Sundar, Stephen Tabiri, Philip Townend, Georgios Tsoulfas, Gabrielle H van Ramshorst, Raghavan Vidya, Dale Vimalachandran, Oliver J Warren, Duane Wedderburn, Naomi Wright, C Allemand, L Boccalatte, M Figari, M Lamm, J Larrañaga, C Marchitelli, F Noll, D Odetto, M Perrotta, J Saadi, L Zamora, C Alurralde, E L Caram, D Eskinazi, J P Mendoza, M Usandivaras, R Badra, A Esteban, J S García, P M García, J I Gerchunoff, S M Lucchini, M A NIgra, L Vargas, T Hovhannisyan, A Stepanyan, T Gould, R Gourlay, B Griffiths, S Gananadha, M McLaren, J Cecire, N Joshi, S Salindera, A Sutherland, J H Ahn, G Charlton, S Chen, N Gauri, R Hayhurst, S Jang, F Jia, C Mulligan, W Yang, G Ye, H Zhang, M Ballal, D Gibson, D Hayne, J Moss, T Richards, P Viswambaram, U G Vo, J Bennetts, T Bright, M Brooke-Smith, R Fong, B Gricks, Y H Lam, B S Ong, M Szpytma, D Watson, K Bagraith, S Caird, E Chan, C Dawson, D Ho, E Jeyarajan, S Jordan, A Lim, G J Nolan, A Oar, D Parker, H Puhalla, A Quennell, L Rutherford, P Townend, M Von Papen, M Wullschleger, A Blatt, D Cope, N Egoroff, M Fenton, J Gani, N Lott, P Pockney, N Shugg, M Elliott, D Phung, D Phan, D Townend, C Bong, J Gundara, A Frankel, S Bowman, G R Guerra, J Bolt, K Buddingh, N N Dudi-Venkata, S Jog, H M Kroon, T Sammour, R Smith, C Stranz, M Batstone, K Lah, W McGahan, D Mitchell, A Morton, A Pearce, M Roberts, G Sheahan, B Swinson, N Alam, S Banting, L Chong, P Choong, S Clatworthy, D Foley, A Fox, M W Hii, B Knowles, J Mack, M Read, A Rowcroft, S Ward, G Wright, M Lanner, I Königsrainer, M Bauer, C Freyschlag, M Kafka, F Messner, D Öfner, I Tsibulak, K Emmanuel, M Grechenig, R Gruber, M Harald, L Öhlberger, J Presl, A Wimmer, I Namazov, E Samadov, D Barker, R Boyce, S Corbin, A Doyle, A Eastmond, R Gill, A Haynes, S Millar, M O'Shea, G Padmore, N Paquette, E Phillips, S St John, K Walkes, N Flamey, P Pattyn, W Oosterlinck, J Van den Eynde, R Van den Eynde, A Gatti, C Nardi, R Oliva, R De Cicco, I Cecconello, P Gregorio, L Pontual Lima, U Ribeiro Junior, F Takeda, R M Terra, M Sokolov, B Kidane, S Srinathan, M Boutros, N Caminsky, G Ghitulescu, G Jamjoum, J Moon, J Pelletier, T Vanounou, S Wong, M Boutros, S Dumitra, A Kouyoumdjian, B Johnston, C Russell, M Boutros, S Demyttenaere, R Garfinkle, J Abou-Khalil, C Nessim, J Stevenson, F Heredia, A Almeciga, A Fletcher, A Merchan, L O Puentes, J Mendoza Quevedo, G Bacic, D Karlovic, D Krsul, M Zelic, I Luksic, M Mamic, B Bakmaz, I Coza, E Dijan, Z Katusic, J Mihanovic, I Rakvin, K Frantzeskou, N Gouvas, G Kokkinos, P Papatheodorou, I Pozotou, O Stavrinidou, A Yiallourou, L Martinek, M Skrovina, I Szubota, J Žatecký, V Javurkova, J Klat, T Avlund, P Christensen, J L Harbjerg, L H Iversen, D W Kjaer, Hø Kristensen, M Mekhael, A L Ebbehøj, P Krarup, N Schlesinger, H Smith, A Abdelsamed, A Y Azzam, H Salem, A Seleim, A Abdelmajeed, M Abdou, N E Abosamak, M Al Sayed, F Ashoush, R Atta, E Elazzazy, M Elhoseiny, M Elnemr, M S Elqasabi, M E Elsayed Hewalla, I Elsherbini, E Essam, M Eweda, I Ghallab, E Hassan, M Ibrahim, M Metwalli, M Mourad, M S Qatora, M Ragab, A Sabry, H Saifeldin, M Saleh Mesbah Mohamed Elkaffas, A Samih, A Samir Abdelaal, S Shehata, K Shenit, D Attia, N Kamal, N Osman, A M Abbas, Has Abd Elazeem, M M Abdelkarem, S Alaa, A K Ali, A Ayman, M G Azizeldine, H Elkhayat, S M Elghazaly, F A Monib, M A Nageh, M M Saad, M Salah, M Shahine, E A Yousof, A Youssef, A Eldaly, M ElFiky, A Nabil, G Amira, I Sallam, M Sherief, A Sherif, A Abdelrahman, H Aboulkassem, G Ghaly, R Hamdy, A Morsi, H Salem, G Sherif, H Abdeldayem, I Abdelkader Salama, M Balabel, Y Fayed, A E Sherif, D Bekele, J Kauppila, E Sarjanoja, O Helminen, H Huhta, J H Kauppila, C Beyrne, L Jouffret, L Lugans, L Marie-Macron, E Chouillard, B De Simone, J Bettoni, S Dakpé, B Devauchelle, N Lavagen, S Testelin, S Boucher, R Breheret, A Gueutier, A Kahn, J KÜn-Darbois, A Barrabe, Z Lakkis, A Louvrier, S Manfredelli, P Mathieu, A Chebaro, V Drubay, M El Amrani, C Eveno, K Lecolle, G Legault, L Martin, G Piessen, F R Pruvot, S Truant, P Zerbib, Q Ballouhey, B Barrat, J Laloze, H Salle, A Taibi, J Usseglio, D Bergeat, A Merdrignac, Roy B Le, L O Perotto, A Scalabre, A Aimé, A Ezanno, B Malgras, P Bouche, S Tzedakis, E Cotte, O Glehen, V Kepenekian, J Lifante, G Passot, A D'Urso, E Felli, D Mutter, P Pessaux, B Seeliger, J Bardet, R Berry, G Boddaert, S Bonnet, E Brian, C Denet, D Fuks, D Gossot, M Grigoroiu, A Laforest, Y Levy-Zauberman, C Louis-Sylvestre, A Moumen, G Pourcher, A Seguin-Givelet, E Tribillon, E Duchalais, F Espitalier, C Ferron, O Malard, U Bork, M Distler, J Fritzmann, J Kirchberg, C Praetorius, C Riediger, J Weitz, T Welsch, P Wimberger, K Beyer, C Kamphues, J Lauscher, F N Loch, C Schineis, M Albertsmeier, M Angele, A Kappenberger, H Niess, T Schiergens, J Werner, R Becker, J Jonescheit, I Pergolini, D Reim, C Boeker, I Hakami, J Mall, P Liokatis, W Smolka, K Nowak, T Reinhard, F Hölzle, A Modabber, P Winnand, M Knitschke, P Kauffmann, S Wolfer, J Kleeff, K Lorenz, C Michalski, U Ronellenfitsch, R Schneider, E Bertolani, A Königsrainer, M W Löffler, M Quante, C Steidle, L ÜberrÜck, C Yurttas, C S Betz, J Bewarder, A Böttcher, S Burg, C Busch, M Gosau, A Heuer, J Izbicki, T O Klatte, D Koenig, N Moeckelmann, C Nitschke, M Priemel, R Smeets, U Speth, S Thole, F G Uzunoglu, T Vollkommer, N Zeller, M J Battista, K Gillen, A Hasenburg, S Krajnak, V Linz, R Schwab, K Angelou, D Haidopoulos, A Rodolakis, P Antonakis, K Bramis, L Chardalias, I Contis, N Dafnios, D Dellaportas, G Fragulidis, A Gklavas, M Konstadoulakis, N Memos, I Papaconstantinou, A Polydorou, T Theodosopoulos, A Vezakis, M I Antonopoulou, D K Manatakis, N Tasis, N Arkadopoulos, N Danias, P Economopoulou, P Kokoropoulos, A Larentzakis, N Michalopoulos, J Selmani, T Sidiropoulos, V Tsaousis, P Vassiliu, K Bouchagier, S Klimopoulos, D Paspaliari, G Stylianidis, K Baxevanidou, K Bouliaris, P Chatzikomnitsa, M Efthimiou, A Giaglaras, C Kalfountzos, G Koukoulis, A M Ntziovara, K Petropoulos, K Soulikia, I Tsiamalou, K Zervas, S Zourntou, I Baloyiannis, A Diamantis, E Gkrinia, J Hajiioannou, C Korais, O Koukoura, K Perivoliotis, A Saratziotis, C Skoulakis, D Symeonidis, K Tepetes, G Tzovaras, D Zacharoulis, V Alexoudi, K Antoniades, I Astreidis, P Christidis, D Deligiannidis, T Grivas, O Ioannidis, I Kalaitsidou, L Loutzidou, A Mantevas, D Michailidou, K Paraskevopoulos, S Politis, A Stavroglou, D Tatsis, I Tilaveridis, K Vahtsevanos, G Venetis, I Karaitianos, T Tsirlis, A Charalabopoulos, T Liakakos, E Mpaili, D Schizas, E Spartalis, A Syllaios, C Zografos, C Anthoulakis, C Christou, V Papadopoulos, A Tooulias, D Tsolakidis, G Tsoulfas, D Zouzoulas, E Athanasakis, E Chrysos, J Tsiaoussis, S Xenaki, E Xynos, K Futaba, M F Ho, S F Hon, Twc Mak, Ssm Ng, C C Foo, B Banky, N Suszták, M Aremu, A Canas-Martinez, O Cullivan, C Murphy, P Owens, L Pickett, L Akmenkalne, J Byrne, M Corrigan, C Cullinane, A Daly, C Fleming, P Jordan, S Killeen, N Lynch, A McCarthy, H Mustafa, S O'Brien, P O'Leary, Was Syed, L Vernon, D Callanan, L Huang, A Ionescu, P Sheahan, I Balasubramanian, M Boland, K Conlon, D Evoy, N Fearon, T Gallagher, J Geraghty, H Heneghan, N Kennedy, D Maguire, D McCartan, E W McDermott, R S Prichard, D Winter, D Alazawi, C Barry, T Boyle, W Butt, E M Connolly, N Donlon, C Donohue, B A Fahey, R Farrell, C Fitzgerald, J Kinsella, J O Larkin, P Lennon, P J Maguire, P Mccormick, B J Mehigan, H Mohan, T Nugent, H O'Sullivan, N Ravi, J V Reynolds, A Rogers, P Shokuhi, J Smith, L A Smith, C Timon, Y Bashir, G Bass, T Connelly, B Creavin, H Earley, J A Elliott, A Gillis, D Kavanagh, P Neary, J O'riordan, I S Reynolds, D Rice, P Ridgway, M Umair, M Whelan, P Carroll, C Collins, K Corless, L Finnegan, A Fowler, A Hogan, M Kerin, A Lowery, P McAnena, K McKevitt, K Nizami, É Ryan, A Samy, J C Coffey, R Cunningham, M Devine, D Nally, C Peirce, S Tormey, N Hardy, P Neary, S O'Malley, M Ryan, S Macina, N M Mariani, E Opocher, A Pisani Ceretti, F Ferrari, F Odicino, E Sartori, C Cotsoglou, S Granieri, F Bianco, A Camillo, M Colledan, S Tornese, M F Zambelli, G Bissolotti, S Fusetti, F Lemma, M V Marino, A Mirabella, G Vaccarella, C Agostini, G Alemanno, I Bartolini, C Bergamini, A Bruscino, C Checcucci, R De Vincenti, A Di Bella, M Fambrini, L Fortuna, G Maltinti, P Muiesan, F Petraglia, P Prosperi, M N Ringressi, M Risaliti, F Sorbi, A Taddei, R Tucci, C Bassi, L Bortolasi, T Campagnaro, L Casetti, M De Pastena, A Esposito, M Fontana, A Guglielmi, L Landoni, G Malleo, G Marchegiani, S Nobile, S Paiella, C Pedrazzani, S Rattizzato, A Ruzzenente, R Salvia, G Turri, M Tuveri, P Bellora, G D'Aloisio, M Ferrari, E Francone, S Gentilli, H Nikaj, M Bianchini, M Chiarugi, F Coccolini, G Di Franco, N Furbetta, D Gianardi, S Guadagni, L Morelli, M Palmeri, D Tartaglia, G Anania, P Carcoforo, M Chiozza, A De Troia, M Koleva Radica, M Portinari, M G Sibilla, A Urbani, N Fabbri, C V Feo, S Gennari, S Parini, E Righini, L Ampollini, L Bellanti, M Bergonzani, G Bertoli, G Bocchialini, G D'Angelo, D Lanfranco, L Musini, T Poli, G P Santoro, A Varazzani, L Aguzzoli, G Borgonovo, C Castro Ruiz, S Coiro, G Falco, V D Mandato, V Mastrofilippo, M T Montella, V Annessi, M Zizzo, U Grossi, S Novello, M Romano, S Rossi, G Zanus, G Esposito, F Frongia, A Pisanu, M Podda, C Belluco, A Lauretta, G Montori, L Moras, M Olivieri, F Bussu, A G Carta, M L Cossu, P Cottu, A Fancellu, C F Feo, G C Ginesu, G Giuliani, M Madonia, T Perra, A Piras, A Porcu, D Rizzo, A M Scanu, A Tedde, M Tedde, P Delrio, D Rega, G Badalamenti, G Campisi, A Cordova, M Franza, G Maniaci, G Rinaldi, F Toia, M Calabrò, F Farnesi, E G Lunghi, A Muratore, N S Pipitone Federico, F Bàmbina, G D'Andrea, P Familiari, V Picotti, G De Palma, G Luglio, G Pagano, F P Tropeano, L Baldari, G A Beltramini, L Boni, E Cassinotti, A Gianni, L Pignataro, S Torretta, C Abatini, M Baia, D Biasoni, G Bogani, P Cadenelli, V Capizzi, Spb Cioffi, D Citterio, L V Comini, M Cosimelli, M Fiore, S Folli, M Gennaro, L Giannini, A Gronchi, M Guaglio, A Macchi, F Martinelli, V Mazzaferro, A Mosca, S Pasquali, C Piazza, F Raspagliesi, L Rolli, R Salvioni, G Sarpietro, C Sarre, L Sorrentino, A Agnes, S Alfieri, F Belia, A Biondi, V Cozza, A D'Amore, D D'Ugo, V De Simone, A Fagotti, G Gasparini, L Gordini, F Litta, C P Lombardi, L Lorenzon, A A Marra, F Marzi, A Moro, A Parello, E Perrone, R Persiani, C Ratto, F Rosa, G Saponaro, G Scambia, O Scrima, G Sganga, R Tudisco, A Belli, V Granata, F Izzo, R Palaia, R Patrone, F M Carrano, M M Carvello, A De Virgilio, F Di Candido, F Ferreli, F Gaino, G Mercante, V Rossi, A Spinelli, G Spriano, D M Donati, T Frisoni, E Palmerini, A Aprile, F Barra, P Batistotti, S Ferrero, P Fregatti, S Scabini, M Sparavigna, E Asti, D Bernardi, L Bonavina, A Lovece, L Adamoli, M Ansarin, S Cenciarelli, F Chu, R De Berardinis, U Fumagalli Romario, F Mastrilli, G Pietrobon, M Tagliabue, E Badellino, A Ferrero, R Massobrio, A De Manzoni Garberini, P Federico, P Maida, E Marra, G Marte, A Petrillo, T Tammaro, A Tufo, M Berselli, G Borroni, E Cocozza, L Conti, M Desio, L Livraghi, V Quintodei, A Rizzi, A Zullo, C Baldi, C Corbellini, G M Sampietro, P Cellerino, E Baldini, P Capelli, L Conti, S M Isolani, M Ribolla, A Bondurri, F Colombo, L Ferrario, C Guerci, A Maffioli, T Armao, M Ballabio, P Bisagni, A Gagliano, M Longhi, M Madonini, P PizziCni, A M Baietti, M Biasini, P Maremonti, F Neri, G M Prucher, S Ricci, F Ruggiero, A G Zarabini, R Barmasse, S Mochet, L Morelli, A Usai, F Bianco, P Incollingo, S Mancini, L Marino Cosentino, A Sagnotta, R Fruscio, T Grassi, L C Nespoli, N Tamini, A Anastasi, B Bartalucci, A Bellacci, G Canonico, L Capezzuoli, C Di Martino, P Ipponi, C Linari, M Montelatici, T Nelli, G Spagni, L Tirloni, A Vitali, E Abate, M Casati, T Casiraghi, L Laface, M Schiavo, A Arminio, A Cotoia, V Lizzi, F Vovola, R Vergari, S D'Ugo, N Depalma, M G Spampinato, P Bartolucci, G Brachini, P Bruzzaniti, A Chiappini, V Chiarella, F Ciccarone, P M Cicerchia, B Cirillo, G De Toma, A Di Bartolomeo, E Fiori, G B Fonsi, G Franco, A Frati, M Giugliano, I Iannone, F La Torre, P Lapolla, C Leonardo, G Marruzzo, S Meneghini, A Mingoli, D Ribuffo, M Salvati, A Santoro, P Sapienza, A K Scafa, L Simonelli, M Zambon, G T Capolupo, F Carannante, M Caricato, G Mascianà, E Mazzotta, A Gattolin, M Migliore, R Rimonda, D Sasia, E Travaglio, M Cervellera, A Gori, L Sartarelli, V Tonini, M Giacometti, S Zonta, A Chessa, A Fiorini, C Norcini, G Colletti, M Confalonieri, A Costanzi, C Frattaruolo, G Mari, M Monteleone, A Bandiera, L Bocciolone, G Bonavina, M Candiani, G Candotti, P De Nardi, F Gagliardi, M Medone, P Mortini, G Negri, P Parise, M Piloni, P Sileri, A Vignali, A Belvedere, P Bernante, P Bertoglio, S Boussedra, E Brunocilla, R Cipriani, G Cisternino, E De Crescenzo, P De Iaco, G Dondi, F Frio, E Jovine, F Mineo Bianchi, J Neri, D Parlanti, A M Perrone, A P Pezzuto, M Pignatti, V Pinto, G Poggioli, M Ravaioli, M Rottoli, R Schiavina, M Serenari, M Serra, P Solli, M Taffurelli, M Tanzanu, M Tesei, T Violante, S Zanotti, F Borghi, D Cianflocca, S Di Maria Grimaldi, D Donati, E Gelarda, P Geretto, G Giraudo, M C Giuffrida, A Marano, S Palagi, L Pellegrino, C Peluso, V Testa, F Agresta, D Prando, M Zese, F Aquila, C Gambacciani, L Lippa, F Pieri, O S Santonocito, G Armatura, G Bertelli, A Frena, P Marinello, F Notte, 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Walker, S Waseem, S Yordanov, T Jones, A Kattakayam, C Loh, R Lunevicius, S Pringle, A Schache, R Shaw, A Sheel, C Rossborough, D Angelou, M Choynowski, B McAree, A McCanny, D Neely, G Tutoveanu, S Ahad, Mfi De La Cruz Monroy, F Mosley, V Oktseloglou, A Alanbuki, M Patel, A Shabana, E Perera, D Raveendran, K Ravi-Shankar, J Thiruchelvam, L Arrowsmith, W Campbell, T Grove, C Kontovounisios, O Warren, P Rolland, A Aggarwal, S Brown, C Jelley, N Neal, R Clifford, N Eardley, E Krishnan, N Manu, E Martin, S Roy Mahapatra, O L Serevina, C Smith, D Vimalachandran, M Bordenave, R Houston, G Putnam, A Robson, H Tustin, K Emslie, P L Labib, A Marchbank, D Miller, G Minto, J Natale, H Nwinee, P Panahi, L Rogers, A Abubakar, M M Akhter Rahman, E Chan, Kyk Ko, H O'Brien, K Sasapu, H Woodun, R Inglis, H J Ng, A De Gea Rico, N Ghazali, J Lambert, G Markose, S Math, I Sarantitis, D Shrestha, A Sultana, M Taggarsi, S Timbrell, O P Vaz, L Vitone, A Day, H Dent, M Fahim, S Waheed, A Hunt, N Laskar, A Gupta, J Steinke, S Thrumurthy, E Massie, K McGivern, D Rutherford, M Wilson, J Hardie, S Kazzaz, S Handa, M Kaushal, A Kler, P Patel, J Redfern, S Tezas, Y Aawsaj, S Amonkar, C Barry, L Blackwell, D Blake, J Carter, H Emerson, A Fisher, M Katory, P Korompelis, W McCormick, A Mustafa, L Pearce, N Ratnavelu, R Reehal, L Kretzmer, L Lalou, B Manku, I Parwaiz, J Stafford, M Abdelkarim, A Asqalan, T Gala, S Ibrahim, A Maw, R Mithany, R Morgan, G Sundaram Venkatesan, K Ang, E J Caruana, M F Chowdhry, A Mohammad, A Nakas, S Rathinam, M Boal, O Brown, S Dwerryhouse, S Higgs, A Vallance, E Boyd, V Irvine, A Kirk, G Bakolas, A Boulton, A Chandock, T Khan, M Kumar, P Agoston, A Bille, B Challacombe, S Fraser, K Harrison-Phipps, J King, G Mehra, L Mills, M Najdy, R Nath, L Okiror, J Pilling, V Rizzo, T Routledge, A Sayasneh, L Stroman, A Wali, M Fehervari, C Fotopoulou, N Habib, S Hamrang-Yousefi, Z Jawad, L Jiao, M Pai, J Ploski, P Rajagopal, S Saso, M Sodergren, D Spalding, S Laws, C Hardie, C McNaught, R Alam, A Budacan, J Cahill, M Kalkat, S Karandikar, L Kenyon, D Naumann, A Patel, J Ayorinde, T Chase, T Cuming, A Ghanbari, L Humphreys, S Tayeh, A Aboelkassem Ibrahim, R Bichoo, H Cao, Akw Chai, J Choudhury, C Evans, H Fitzjohn, H Ikram, M Langstroth, M Loubani, A McMillan, S Nazir, Ssa Qadri, A Robinson, E Ross, T Sehgal, A Wilkins, J Dixon, J Dunning, K Freystaetter, M Jha, S Lester, A Madhavan, S V Thulasiraman, Y Viswanath, T Curl-Roper, C Delimpalta, Ccl Liao, V Velchuru, E Westwood, E Belcher, G Bond-Smith, S Chidambaram, F Di Chiara, K Fasanmade, L Fraser, H Fu, M Ganau, S Gore, J Graystone, D Jeyaretna, H Khatkar, M Lami, M Maher, S Mastoridis, R Mihai, R Piper, S Prabhu, Obf Risk, U Selbong, K Shah, R Smillie, H Soleymani Majd, S Sravanam, D Stavroulias, G D Tebala, M Vatish, C Verberne, K Wallwork, S Winter, M I Bhatti, H Boyd-Carson, E Elsey, E Gemmill, P Herrod, M Jibreel, E Lenzi, T Saafan, D Sapre, T Sian, N Watson, A Athanasiou, G Bourke, L Bradshaw, A Brunelli, J Burke, P Coe, F Costigan, H Elkadi, M Ho, J Johnstone, A Kanatas, V Kantola, A Kaufmann, A Laios, S Lam, E MacInnes, S Munot, C Nahm, M Otify, C Pompili, I Smith, G Theophilou, G Toogood, R Wade, D Ward, C West, S Annamalai, C Ashmore, A Boddy, T Hossain, A Kourdouli, A Gvaramadze, A Jibril, L Prusty, D Thekkinkattil, A Harky, M Shackcloth, A Askari, C Chan, N Cirocchi, S Kudchadkar, K Patel, J Sagar, S Shaw, R Talwar, M Abdalla, R Edmondson, O Ismail, D Jones, K Newton, N Stylianides, A Aderombi, U Andaleeb, O Bajomo, K Beatson, W Garrett, M Mehmood, V Ng, R Al-Habsi, G S Divya, B Keeler, B Al-Sarireh, R Egan, R Harries, A Henry, M Kittur, Z Li, K Parkins, F Soliman, N Spencer, D Thompson, C Burgess, C Gemmell, C Grieco, M Hollyman, L Hunt, J Morrison, S Ojha, N Ryan, F Abbadessa, S Barnard, C Chan, N Dawe, J Hammond, Ali F Mahmoud, I McPherson, C Mellor, J Moir, S Pandanaboyana, J Powell, B Rai, A Rogers, C Roy, A Sachdeva, C Saleh, S Tingle, T Williams, J Manickavasagam, C McDonald, N McGrath, N McSorley, K Ragupathy, L Ramsay, A Solth, O Kakisi, K Seebah, I Shaikh, L Sreedharan, M Youssef, J Shah, P Ameerally, N McLarty, S Mills, A Shenfine, K Sahnan, J Abu, E Addae-Boateng, D Bratt, L Brock, N Burnside, S Cadwell-Sneath, K Gajjar, C Gan, C Grundy, K Hallam, K Hassell, M Hawari, A Joshi, H Khout, K Konstantinidi, Rxn Lee, D Nunns, R Schiemer, T Walton, H Weaver, L Whisker, K Williamson, J McVeigh, R Myatt, M A Williams, R Kaur, E Leung, S Sundar, M Michel, S Patil, S Ravindran, J Sarveswaran, L Scott, M Edmond, E King, M Almond, A Bhangu, O Breik, L D Cato, A Desai, S Ford, E Griffiths, M Idle, M Kamal, A Kisiel, R Kulkarni, Jkc Mak, T Martin, P Nankivell, A Parente, S Parmar, A M Pathanki, L Phelan, P Praveen, S Saeed, N Sharma, J Singh, F Tirotta, D Vijayan, A Geddes, J McCaul, J McMahon, A H Khan, F Khan, A Mansuri, S Mukherjee, M Patel, M Sarigul, S Singh, K L Tan, A Woodham, A Adiamah, H Brewer, A Chowdhury, J Evans, D Humes, J Jackman, A Koh, C Lewis-Lloyd, O Oyende, J Reilly, D Worku, P Cool, G Cribb, K Shepherd, C Bisset, S Moug, N Elson, G Faulkner, P Saleh, C Underwood, G Brixton, L Findlay, T Klatte, A Majkowska, J Manson, R Potter, A Bhalla, Z Chia, P Daliya, A Goyal, E Grimley, A Hamad, A Kumar, F L Malcolm, E Theophilidou, J Bowden, N Campain, I Daniels, C Evans, G Fowler, J John, L Massey, F McDermott, J McGrath, A McLennan, M Ng, J Pascoe, N Rajaretnam, S Bulathsinhala, B Davidson, G Fusai, C Hidalgo Salinas, N Machairas, T Pissanou, J M Pollok, D A Raptis, F Soggiu, H Tzerbinis, S E Xyda, A Beamish, E Davies, R Foulkes, D Magowan, H Nassa, R Ooi, C Price, L Smith, F Solari, A Tang, G Williams, Y Al-Tamimi, A Bacon, N Beasley, D Chew, M Crank, N Ilenkovan, M Macdonald, B Narice, O Rominiyi, A Thompson, I Varley, T Drake, E Harrison, G Linder, J Mayes, R McGregor, R Skipworth, V Zamvar, E Davies, P Hawkin, T Raymond, O Ryska, R Baron, D Dunne, S Gahunia, C Halloran, N Howes, R McKinney, F McNicol, J Russ, P Szatmary, J R Tan, A Thomas, P Whelan, A Anzak, A Banerjee, O Fuwa, F Hughes, J D Jayasinghe, C Knowles, H Kocher, I Leal Silva, F S Ledesma, A Minicozzi, L Navaratne, R Rahman, R Ramamoorthy, C Sohrabi, M Thaha, B Thakur, M Venn, V Yip, R Baumber, J Parry, S Evans, L Jeys, G Morris, M Parry, J Stevenson, N Ahmadi, G Aresu, Z M Barrett-Brown, A S Coonar, H Durio Yates, D Gearon, J Hogan, M King, A Peryt, I S Pradeep, C Smith, M Adishesh, R Atherton, K Baxter, M Brocklehurst, M Chaudhury, N Krishnamohan, J McAleer, G Owens, E Parkin, P Patkar, I Phang, A Aladeojebi, M Ali, B Barmayehvar, A Gaunt, M Gowda, E Halliday, M Kitchen, F Mansour, M Thomas, D Zakai, N Abbassi-Ghadi, H Assalaarachchi, A Currie, M Flavin, A Frampton, M Hague, C Hammer, J Hopper, J Horsnell, S Humphries, A Kamocka, T K Madhuri, S Preston, P Singh, J Stebbing, A Tailor, D Walker, F Aljanadi, M Jones, P Mhandu, C O'Donnell, R Turkington, Z Al-Ishaq, S Bhasin, A S Bodla, A Burahee, A Crichton, R Fossett, N Pigadas, S Pickford, E Rahman, D Snee, R Vidya, N Yassin, F Colombo, D Fountain, M T Hasan, K Karabatsou, R Laurente, O Pathmanaban, A Al-Mukhtar, S Brown, J Edwards, A Giblin, C Kelty, M Lee, G Lye, T Newman, A Sharkey, C Steele, N Sureshkumar Shah, E Whitehall, R Athwal, A Baker, L Jones, C Konstantinou, S Ramcharan, S Singh, J Vatish, R Wilkin, M Ethunandan, G K Sekhon, H Shields, R Singh, F Wensley, S Lawday, A Lyons, T Abbott, S Anwar, K Ghufoor, C Sohrabi, E Chung, R Hagger, A Hainsworth, A Karim, H Owen, A Ramwell, K Williams, C Baker, A Davies, J Gossage, M Kelly, W Knight, J Hall, G Harris, G James, C Kang, D J Lin, A D Rajgor, T Royle, R Scurrah, B Steel, L J Watson, D Choi, R Hutchison, A Jain, V Luoma, H Marcus, R May, A Menon, B Pramodana, L Webber, I A Aneke, P Asaad, B Brown, J Collis, S Duff, A Khan, F Moura, B Wadham, H Warburton, T Elmoslemany, M Jenkinson, C Millward, R Zakaria, S Mccluney, C Parmar, S Shah, J Allison, M S Babar, B Collard, S Goodrum, K Lau, A Patel, R Scott, E Thomas, H Whitmore, D Balasubramaniam, B Jayasankar, S Kapoor, A Ramachandran, A Elhamshary, Smb Imam, K Kapriniotis, V Kasivisvanathan, J Lindsay, S Rakhshani-Moghadam, N Beech, M Chand, L Green, N Kalavrezos, H Kiconco, R McEwen, C Schilling, D Sinha, J Pereca, J Singh, S Chopra, D Egbeare, R Thomas, T Combellack, Sef Jones, M Kornaszewska, M Mohammed, A Sharma, G Tahhan, V Valtzoglou, J Williams, P Eskander, K Gash, L Gourbault, M Hanna, T Maccabe, C Newton, J Olivier, S Rozwadowski, E Teh, D West, H Al-Omishy, M Baig, H Bates, G Di Taranto, K Dickson, N Dunne, C Gill, D Howe, D Jeevan, A Khajuria, K Martin-Ucar AMcEvoy, P Naredla, V Ng, S Robertson, M Sait, D R Sarma, S Shanbhag, T Shortland, S Simmonds, J Skillman, N Tewari, G Walton, M A Akhtar, A Brunt, J McIntyre, K Milne, M M Rashid, A Sgro, K E Stewart, A Turnbull, M Aguilar Gonzalez, S Talukder, C Boyle, D Fernando, K Gallagher, A Laird, D Tham, M Bath, P Patki, C Sohrabi, C Tanabalan, T Arif, C Magee, T Nambirajan, S Powell, R Vinayagam, I Flindall, A Hanson, V Mahendran, S Green, M Lim, L MacDonald, V Miu, L Onos, K Sheridan, R Young, F Alam, O Griffiths, C Houlden, R Jones, V S Kolli, A K Lala, S Leeson, R Peevor, Z Seymour, L Chen, E Henderson, A Loehrer, K Brown, D Fleming, A Haynes, C Heron, C Hill, H Kay, E Leede, K McElhinney, K Olson, E C Osterberg, C Riley, P Srikanth, M Thornhill, D Blazer, G DiLalla, E S Hwang, W Lee, M Lidsky, J Plichta, L Rosenberger, R Scheri, K Shah, K Turnage, J Visgauss, S Zani, J Farma, J Clark, D Kwon, E Etchill, H E Gabre-Kidan AJenny, A Kent, M Ladd, C Long, H Malapati, A Margalit, S Rapaport, J Rose, K Stevens, L Tsai, D Vervoort, P Yesantharao, A Dehal, D Klaristenfeld, K Huynh, L Brown, I Ganly, J Mullinax, N Gusani, J Hazelton, J Maines, J S Oh, A Ssentongo, P Ssentongo, M Azam, A Choudhry, W Marx, J Fleming, A Fuson, J Gigliotti, A Ovaitt, Y Ying, M K Abel, V Andaya, K Bigay, M A Boeck, L Chen, H Chern, C Corvera, I El-Sayed, A Glencer, P Ha, Bcs Hamilton, C Heaton, K Hirose, D M Jablons, K Kirkwood, L Z Kornblith, J R Kratz, R Lee, P N Miller, E Nakakura, B Nunez-Garcia, R O'Donnell, D Ozgediz, P Park, B Robinson, A Sarin, B Sheu, M Varma, K Wai, R Wustrack, M J Xu, D Beswick, J Goddard, J Manor, J Song, T Fullmer, C Gaskill, N Gross, K Kiong, C L Roland, S N Zafar, M Abdallah, A Abouassi, M Almasri, G Kulkarni, H Marwan, M Mehdi, S Aoun, V S Ban, H H Batjer, J Caruso, D Abbott, A Acher, T Aiken, J Barrett, E Foley, P Schwartz, S N Zafar, A Hawkins, A Maiga, J Laufer, S Scasso
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Aged, 80 and over ,Male ,Critical Care ,SARS-CoV-2 ,International Cooperation ,COVID-19 ,Middle Aged ,Cohort Studies ,Logistic Models ,Postoperative Complications ,Elective Surgical Procedures ,Neoplasms ,Outcome Assessment, Health Care ,Humans ,Female ,Epidemics ,Aged - Abstract
PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.
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- 2021
4. Angiogenin-Functionalized Gold Nanoparticles-Graphene Oxide Nanohybrids for Wound Care Application
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Cucci, L., Riela, L., Hansson, O., Marzo, T., Satriano, C., and La Mendola, D.
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- 2021
5. Interaction of gold N-heterocyclic carbenes with nucleic acids
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Biver, T., Gabbiani, C., Pescitelli, G., Marzo, T., Bazzicalupi, C., Gratteri, P., Messori, L., and Guarra, F.
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- 2018
6. The combined activation of K Ca 3.1 and inhibition of K v 11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
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Pillozzi, S, D'Amico, M, Bartoli, G, Gasparoli, L, Petroni, G, Crociani, O, Marzo, T, Guerriero, A, Messori, L, Severi, M, Udisti, R, Wulff, H, Chandy, KG, Becchetti, A, and Arcangeli, A
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preclinical mouse models ,Riluzole ,Cisplatin uptake ,SKA-31 ,E4031 - Abstract
Background:Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K + channel modulators on colorectal cancer (CRC) cells.Methods:The functional expression of Ca 2+ -activated (K Ca 3.1, also known as KCNN4) and voltage-dependent (K v 11.1, also known as KCNH2 or hERG1) K + channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K + channel modulators were tested in vitro for their action on K + currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance.Results:Cisplatin-resistant CRC cells expressed higher levels of K Ca 3.1 and K v 11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, K Ca 3.1 activators (SKA-31) and K v 11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when K Ca 3.1 activation and K v 11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate K Ca 3.1 and inhibit K v 11.1. Cisplatin uptake into resistant cells depended on K Ca 3.1 channel activity, as it was potentiated by K Ca 3.1 activators. K v 11.1 blockade led to increased K Ca 3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a K Ca 3.1 activator and a K v 11.1 inhibitor also overcame Cisplatin resistance in vivo.Conclusions:As Riluzole, an activator of K Ca 3.1 and inhibitor of K v 11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.
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- 2018
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7. The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
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Pillozzi, S, D'Amico, M, Bartoli, G, Gasparoli, L, Petroni, G, Crociani, O, Marzo, T, Guerriero, A, Messori, L, Severi, M, Udisti, R, Wulff, H, Chandy, K, Becchetti, A, Arcangeli, A, Pillozzi, S, D'Amico, M, Bartoli, G, Gasparoli, L, Petroni, G, Crociani, O, Marzo, T, Guerriero, A, Messori, L, Severi, M, Udisti, R, Wulff, H, Chandy, K, Becchetti, A, and Arcangeli, A
- Abstract
BACKGROUND: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K+ channel modulators on colorectal cancer (CRC) cells. METHODS: The functional expression of Ca2+-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11.1, also known as KCNH2 or hERG1) K+ channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K+ channel modulators were tested in vitro for their action on K+ currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. RESULTS: Cisplatin-resistant CRC cells expressed higher levels of KCa3.1 and Kv11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, KCa3.1 activators (SKA-31) and Kv11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when KCa3.1 activation and Kv11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate KCa3.1 and inhibit Kv11.1. Cisplatin uptake into resistant cells depended on KCa3.1 channel activity, as it was potentiated by KCa3.1 activators. Kv11.1 blockade led to increased KCa3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a KCa3.1 activator and a Kv11.1 inhibitor also overcame Cisplatin resistance in vivo. CONCLUSIONS: As Riluzole, an activator of KCa3.1 and inhibitor of Kv11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC
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- 2018
8. PtI2(DACH), the iodido analogue of oxaliplatin as a candidate for colorectal cancer treatment: chemical and biological features
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Cirri, D., primary, Pillozzi, S., additional, Gabbiani, C., additional, Tricomi, J., additional, Bartoli, G., additional, Stefanini, M., additional, Michelucci, E., additional, Arcangeli, A., additional, Messori, L., additional, and Marzo, T., additional
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- 2017
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9. Rational drug design paradigms: the odyssey for designing better drugs
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T Kellici D Ntountaniotis E Vrontaki G Liapakis P Moutevelis-Minakakis G Kokotos S Hadjikakou AG Tzakos A Afantitis G Melagraki S Bryant T Langer V Di Marzo T Mavromoustakos
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Θετικές Επιστήμες ,Science - Abstract
Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.
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- 2015
10. Cytotoxic activity and protein binding through an unusual oxidative mechanism by an iridium(i)–NHC complex
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Gothe, Y., primary, Marzo, T., additional, Messori, L., additional, and Metzler-Nolte, N., additional
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- 2015
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11. PtI2(DACH), the iodido analogue of oxaliplatin as a candidate for colorectal cancer treatment: chemical and biological features.
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Cirri, D., Pillozzi, S., Gabbiani, C., Tricomi, J., Bartoli, G., Stefanini, M., Michelucci, E., Arcangeli, A., Messori, L., and Marzo, T.
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COLON cancer treatment ,OXALIPLATIN ,PHYSIOLOGICAL effects of platinum ,THERAPEUTICS - Abstract
Colorectal cancer (CRC) is a global health problem being the fourth most common cause of death due to cancer worldwide. Oxaliplatin plays a key role in current CRC treatment but shows serious drawbacks, such as a high systemic toxicity and the frequent insurgence of Pt resistance. In search of novel and more efficacious Pt-based drugs for CRC treatment, we synthesized and characterised PtI
2 (DACH), an oxaliplatin analogue. PtI2 (DACH) was obtained through the replacement of bidentate oxalate with two iodides. PtI2 (DACH) turned out to be more lipophilic than oxaliplatin, a fact that led to an enhancement of its cellular uptake. In contrast to oxaliplatin, PtI2 (DACH) showed a scarce reactivity towards model proteins, while maintaining affinity for a standard DNA oligo. Notably, PtI2 (DACH) induced cytotoxicities roughly comparable to those of oxaliplatin in three representative CRC cell lines. Moreover, it was able to trigger cell apoptosis, to an extent even better than cisplatin and oxaliplatin. Overall, a rather promising picture emerges for this novel Pt drug that merits, in our opinion, a deeper and more extensive preclinical evaluation. [ABSTRACT FROM AUTHOR]- Published
- 2017
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12. The first step of arsenoplatin-1 aggregation in solution unveiled by solving the crystal structure of its protein adduct
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Giarita Ferraro, Alessandro Pratesi, Damiano Cirri, Luigi Messori, Antonello Merlino, Tiziano Marzo, Ferraro, G., Cirri, D., Marzo, T., Pratesi, A., Messori, L., and Merlino, A.
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Aqueous solution ,Molecular Structure ,Arsenites ,chemistry.chemical_element ,Antineoplastic Agents ,Trimer ,Crystal structure ,Oligomer ,Adduct ,Solutions ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Arsenic Trioxide ,chemistry ,Coordination Complexes ,Moiety ,Muramidase ,Cisplatin ,Lysozyme ,Platinum ,Protein Binding - Abstract
Arsenoplatin-1 (AP-1) is an innovative dual-action anticancer agent that contains a platinum(ii) center coordinated to an arsenous acid moiety. We found that AP-1 spontaneously aggregates in aqueous solutions generating oligomeric species of increasing length. Afterward, we succeeded in solving the crystal structure of the adduct formed between the model protein lysozyme and an early AP-1 oligomer that turned out to be a trimer. Remarkably, this crystal structure traps an early stage of AP-1 aggregation offering detailed insight into the molecular process of the oligomer's growth.
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- 2021
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13. Oxaliplatin inhibits angiogenin proliferative and cell migration effects in prostate cancer cells
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Lorena Maria Cucci, Örjan Hansson, Tiziano Marzo, Giarita Ferraro, Diego La Mendola, Alessandro Pratesi, Cristina Satriano, Antonello Merlino, Marzo, T., Ferraro, G., Cucci, L. M., Pratesi, A., Hansson, O., Satriano, C., Merlino, A., and La Mendola, D.
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Male ,Angiogenin ,Angiogenesis ,Biochemistry ,law.invention ,Inorganic Chemistry ,Neoplasm Protein ,Ribonuclease ,Prostate cancer ,Confocal microscopy ,law ,Cell Movement ,medicine ,Humans ,Platinum ,X-ray crystallography ,Cell Proliferation ,Mass spectrometry ,Pancreatic ,Cell growth ,Chemistry ,PC-3 Cell ,Cancer ,Prostatic Neoplasms ,Cell migration ,Ribonuclease, Pancreatic ,medicine.disease ,Oxaliplatin ,Neoplasm Proteins ,Angiogenesi ,PC-3 Cells ,Cancer research ,medicine.drug ,Human - Abstract
Angiogenin (Ang) is a potent angiogenic protein that is overexpressed in many types of cancer at concentration values correlated to the tumor aggressiveness. Here, by means of an integrated multi-technique approach based on crystallographic, spectrometric and spectroscopic analyses, we demonstrate that the anti-cancer drug oxaliplatin efficiently binds angiogenin. Microscopy cellular studies, carried out on the prostate cancer cell (PC-3) line , show that oxaliplatin inhibits the angiogenin prompting effect on cell proliferation and migration, which are typical features of angiogenesis process. Overall, our findings point to angiogenin as a possible target of oxaliplatin, thus suggesting a potential novel mechanism for the antineoplastic activity of this platinum drug and opening the avenue to novel approaches in the combined anti-cancer anti-angiogenic therapy.
- Published
- 2022
14. Arsenoplatin-1 Is a Dual Pharmacophore Anticancer Agent
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Tiziano Marzo, Andrew P. Mazar, Giarita Ferraro, Richard W. Ahn, Luigi Messori, Sara Abuhadba, Đenana Miodragović, Thomas V. O'Halloran, Antonello Merlino, Abraham Bogachkov, Elden P. Swindell, Miodragovic, D., Merlino, A., Swindell, E. P., Bogachkov, A., Ahn, R. W., Abuhadba, S., Ferraro, G., Marzo, T., Mazar, A. P., Messori, L., and O'Halloran, T. V.
- Subjects
Organoplatinum Compounds ,cisplatin ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Arsenic Trioxide ,Cell Line, Tumor ,protein metalation, cancer research, metallodrugs ,Hydrolase ,Arsenoplatin ,Arsenous acid ,medicine ,Humans ,cancer ,Structure–activity relationship ,Arsenic trioxide ,Cell Proliferation ,Cisplatin ,Dose-Response Relationship, Drug ,Molecular Structure ,General Chemistry ,AP-1 ,Combinatorial chemistry ,0104 chemical sciences ,anticancer drugs ,Arsenoplatin, AP-1, cancer, anticancer drugs, cisplatin, trisenox, NCI-60 ,trisenox ,chemistry ,Cell culture ,Drug Screening Assays, Antitumor ,Pharmacophore ,DNA ,NCI-60 ,medicine.drug - Abstract
Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP1), [Pt(μ-NHC(CH(3))O)(2)ClAs(OH)(2)], the first representative of this novel class of anti-cancer agents, displays a superior activity profile relative to the parent drugs As(2)O(3) or cisplatin in majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules – proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nε of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)(2) moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
- Published
- 2019
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15. Synthesis, DNA binding studies, and antiproliferative activity of novel Pt(II)-complexes with an L-alanyl-based ligand
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Domenica Capasso, Luigi Messori, Daniela Montesarchio, Tiziano Marzo, Chiara Platella, Claudia Riccardi, Domenica Musumeci, Alessandro Pratesi, Giovanna M. Rozza, Sonia Di Gaetano, Giovanni N. Roviello, Riccardi, C., Capasso, D., Rozza, G. M., Platella, C., Montesarchio, D., Di Gaetano, S., Marzo, T., Pratesi, A., Messori, L., Roviello, G. N., and Musumeci, D.
- Subjects
Stereochemistry ,ESI-MS spectrometry ,chemistry.chemical_element ,Antineoplastic Agents ,010402 general chemistry ,Ligands ,01 natural sciences ,Biochemistry ,Inorganic Chemistry ,Metal ,chemistry.chemical_compound ,NMR spectroscopy ,Coordination Complexes ,Cell Line, Tumor ,Side chain ,Moiety ,Humans ,DNA binding ,Platinum ,chemistry.chemical_classification ,Alanine ,010405 organic chemistry ,CD spectroscopy ,Nuclear magnetic resonance spectroscopy ,DNA ,0104 chemical sciences ,Amino acid ,G-Quadruplexes ,Pt(II)-complexes ,Triazolyl-thione L-alanine ligand ,Propanoic acid ,chemistry ,visual_art ,triazolyl-thione L-alanine ligand ,visual_art.visual_art_medium ,Drug Screening Assays, Antitumor ,Pt(II)-complexe - Abstract
An artificial alanine-based amino acid {(S)-2-amino-3-[4-propyl-3-(thiophen-2-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoic acid, here named TioxAla}, bearing a substituted triazolyl-thione group on the side chain and able to bind RNA biomedical targets, was here chosen as a valuable scaffold for the synthesis of new platinum complexes with potential dual action owing to the concomitant presence of the metal centre and the amino acid moiety. Three new platinum complexes, obtained from the reaction of TioxAla with K2PtCl4, were characterized by mass spectrometry, nuclear magnetic resonance and UV–vis spectroscopy: one compound (Pt1, bis-{(S)-2-amino-3-[4-propyl-3-(thiophen-2-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoate-O,S} platinum(II)) consisted of two amino acid units coordinating the Pt(II) ion; the other two, Pt2 [potassium dichloro-{(S)-2-amino-3-[4-propyl-3-(thiophen-2-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoate (O,S)} platinum(II)] and Pt3 [potassium dichloro-{(S)-2-amino-3-[4-propyl-3-(thiophen-2-yl)-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoate (O,N)} platinum(II)], were isomers bearing one TioxAla unit, and two chlorides as Pt-ligands. Pt coordination involved preferentially the amino, carboxylic and thione functions of TioxAla. By preliminary antiproliferative assays, a moderate cytotoxic activity on cancer cells was observed only for Pt2 and Pt3, while no anticancer activity was found for both the chloride-free complex (Pt1) and TioxAla. This cytotoxicity, however lower than that of cisplatin, well correlated with the marked ability, here found only for Pt2 and Pt3 complexes, to bind DNA sequences either in random coil or in structured forms (duplex and G-quadruplex), as verified by spectroscopic and spectrometric analysis.
- Published
- 2019
16. The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells
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Massimo D'Amico, Luca Gasparoli, Mirko Severi, Tiziano Marzo, Giulia Petroni, Olivia Crociani, Gianluca Bartoli, Luigi Messori, Angela Guerriero, Heike Wulff, Serena Pillozzi, Annarosa Arcangeli, Andrea Becchetti, K. George Chandy, Roberto Udisti, Pillozzi, S, D'Amico, M, Bartoli, G, Gasparoli, L, Petroni, G, Crociani, O, Marzo, T, Guerriero, A, Messori, L, Severi, M, Udisti, R, Wulff, H, Chandy, K, Becchetti, A, Arcangeli, A, and Lee Kong Chian School of Medicine (LKCMedicine)
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,ERG1 Potassium Channel ,preclinical mouse models ,Cell ,Drug Resistance ,Apoptosis ,Mice ,BIO/09 - FISIOLOGIA ,Riluzole ,SKA-31 ,E4031 ,Cisplatin uptake ,Cancer ,Tumor ,Chemistry ,Cell Cycle ,Drug Synergism ,Cell cycle ,Intermediate-Conductance Calcium-Activated Potassium Channels ,Colo-Rectal Cancer ,medicine.anatomical_structure ,5.1 Pharmaceuticals ,Public Health and Health Services ,Development of treatments and therapeutic interventions ,Colorectal Neoplasms ,HT29 Cells ,medicine.drug ,medicine.medical_specialty ,Cell Survival ,Oncology and Carcinogenesis ,Cell Line ,03 medical and health sciences ,KCNN4 ,Inhibitory Concentration 50 ,In vivo ,Internal medicine ,medicine ,Potassium Channel Blockers ,Animals ,Humans ,Medicine [Science] ,Benzothiazoles ,Oncology & Carcinogenesis ,Cisplatin ,Activator (genetics) ,HCT116 Cells ,030104 developmental biology ,Cell culture ,Cancer research ,Pyrazoles ,Neoplasm ,cisplatin, KCa, hERG, colorectal cancer, chemoresistance ,Digestive Diseases - Abstract
Background: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K+ channel modulators on colorectal cancer (CRC) cells. Methods: The functional expression of Ca2+-activated (KCa3.1, also known as KCNN4) and voltage-dependent (Kv11.1, also known as KCNH2 or hERG1) K+ channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K+ channel modulators were tested in vitro for their action on K+ currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance. Results: Cisplatin-resistant CRC cells expressed higher levels of KCa3.1 and Kv11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, KCa3.1 activators (SKA-31) and Kv11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when KCa3.1 activation and Kv11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate KCa3.1 and inhibit Kv11.1. Cisplatin uptake into resistant cells depended on KCa3.1 channel activity, as it was potentiated by KCa3.1 activators. Kv11.1 blockade led to increased KCa3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a KCa3.1 activator and a Kv11.1 inhibitor also overcame Cisplatin resistance in vivo. Conclusions: As Riluzole, an activator of KCa3.1 and inhibitor of Kv11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC. Published version
- Published
- 2018
17. Oxaliplatin vs. cisplatin: competition experiments on their binding to lysozyme
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Antonello Merlino, Daniela Marasco, Luigi Messori, Tiziano Marzo, Marasco, Daniela, Messori, L, Marzo, T, and Merlino, Antonello
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Spectrometry, Mass, Electrospray Ionization ,Resolution (mass spectrometry) ,Organoplatinum Compounds ,Stereochemistry ,platinum complex ,cisplatin ,oxaliplatin, thermal shift assay ,Antineoplastic Agents ,Plasma protein binding ,protein binding ,Adduct ,Inorganic Chemistry ,chemistry.chemical_compound ,Hydrolase ,medicine ,Surface plasmon resonance ,hen egg lysozyme ,lysozyme ,antineoplastic agent ,Cisplatin ,Binding Sites ,Crystallography ,Circular Dichroism ,oxaliplatin ,Surface Plasmon Resonance ,Oxaliplatin ,chemistry ,Muramidase ,Lysozyme ,medicine.drug - Abstract
The model protein hen egg white lysozyme was challenged with oxaliplatin and cisplatin. ESI mass spectrometry, surface plasmon resonance and thermal shift analyses demonstrate the formation of a bis-platinum adduct, though in very small amounts. Crystals of the bis-platinum adduct were obtained using two different preparations and the X-ray structures were solved at 1.85 A and 1.95 A resolution. Overall, the obtained data point out that, under the analyzed conditions, the two Pt drugs have similar affinities for the protein, but bind on its surface at two non-overlapping sites. In other words, these two drugs manifest a significantly different reactivity with this model protein and do not compete for the same protein binding sites.
- Published
- 2015
18. Peculiar Features in the Crystal Structure of the Adduct Formed between cis-PtI2(NH3)2 and Hen Egg White Lysozyme
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Chiara Gabbiani, Luigi Messori, Adoración G. Quiroga, Tiziano Marzo, Antonello Merlino, Amparo A. Valdes, Messori, L, Marzo, T, Gabbiani, C, Valdes, Aa, Quiroga, Ag, and Merlino, Antonello
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Models, Molecular ,Spectrometry, Mass, Electrospray Ionization ,Stereochemistry ,Electrospray ionization ,Iodide ,chemistry.chemical_element ,Crystal structure ,Crystallography, X-Ray ,CYTOCHROME-C ,Adduct ,Inorganic Chemistry ,chemistry.chemical_compound ,X-RAY-DIFFRACTION ,SUPEROXIDE-DISMUTASE ,Imidazole ,Physical and Theoretical Chemistry ,Platinum ,chemistry.chemical_classification ,ANTICANCER PLATINUM DRUGS ,Ligand ,ESI MASS-SPECTROMETRY ,CARBOPLATIN BINDING ,PROTEIN INTERACTIONS ,CISPLATIN ,HISTIDINE ,COMPLEXES ,chemistry ,Muramidase ,Cisplatin ,Lysozyme - Abstract
The r eactivity o f cis - diamminediiodidoplatinum(II), cis-PtI2(NH3)2, the iodo analogue of cisplatin, with hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry and X-ray crystallography. Interestingly, the study compound forms a stable 1:1 protein adduct for which the crystal structure was solved at 1.99 A resolution. In this adduct, the Pt II center, upon release of one ammonia ligand, selectively coordinates to the imidazole of His15. Both iodide ligands remain bound to platinum, with this being a highly peculiar and unexpected feature. Notably, two equivalent modes of Pt II binding are possible that differ only in the location of I atoms with respect to ND1 of His15. The structure of the adduct was compared with that of HEWL−cisplatin, previously described; differences are stressed and their important mechanistic implications discussed.
- Published
- 2013
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19. Detailed mechanism of a DNA/RNA nucleobase substituting bridging ligand in diruthenium(II,III) and dirhodium(II,II) tetraacetato paddlewheel complexes: protonation of the leaving acetate is crucial.
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Tolbatov I, Marzo T, Umari P, La Mendola D, and Marrone A
- Abstract
Paddlewheel complexes of bimetallic scaffolds are emerging metallic agents in the bioinorganic chemistry landscape. In the most commonly employed construct, these complexes are decorated by the carboxylate moiety, prompting their possible deployment to target either protein or nucleic acid targets. In this study, density functional investigation was performed to assess viable mechanistic routes for the substitution of one acetate ligand with one chelating purine, i.e. adenine or guanine, in diruthenium and dirhodium tetraacetate paddlewheel complexes. This study evidenced the relevant stages of the process at an atomistic scale of resolution and provided for the encompassed rate-determining chemical events. Therefore, calculations indicated that acetate decomplexation as well as the concomitant nucleobase bridging proceeded gradually via a multistep process that included protonation of the leaving acetate. The present picture of the mechanism is envisioned to be relevant to the design and interpretation of experiments focused on the reaction of diruthenium and/or dirhodium tetracarboxylate complexes with nucleobases and eventuating in the formation of either nucleobase bridged-complexes or in the dismantling of the bimetallic construct.
- Published
- 2024
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20. Dimolybdenum (II,II) paddlewheel complexes bearing non-steroidal anti-inflammatory drug ligands: Insights into the chemico-physical profile and first biological assessment.
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Chiaverini L, Notarstefano V, Tolbatov I, Umari P, Giorgini E, Ciccone L, Di Leo R, Trincavelli L, Giacomelli C, Marchetti L, Marzo T, La Mendola D, and Marrone A
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- Ligands, Humans, Naproxen chemistry, Animals, Ibuprofen chemistry, Aspirin chemistry, Indomethacin chemistry, Mice, Anti-Inflammatory Agents, Non-Steroidal chemistry, Molybdenum chemistry, Coordination Complexes chemistry
- Abstract
Multinuclear complexes are metal compounds featured by adjacent bound metal centers that can lead to unconventional reactivity. Some M
2 L4 -type paddlewheel dinuclear complexes with monoanionic bridging ligands feature promising properties, including therapeutic ones. Molybdenum has been studied for the formation of multiple-bonded M2+ compounds due to their unique scaffold, redox, and spectroscopic properties as well as for applications in several fields including catalysis and biology. These latter are much less explored and only sporadic studies have been carried out. Here, a series of four dimolybdenum (II,II) carboxylate paddlewheel complexes were synthesized using different Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) as ligands. The reaction of (NH4 )5 [Mo2 Cl9 ]·H2 O with the selected NSAIDs in methanol produced the complexes Mo2 (μ-O2 CR)4 where RCO2 is ibuprofen (1), naproxen (2), aspirin (3) and indomethacin (4). The products were obtained in good yields and extensively characterized with integrated techniques. Stability and solution behaviour were studied using a mixed experimental and computational approach. Finally, the biological activity of 1 and 3 (i.e. the most reactive and the most stable compounds of the series, respectively) was preliminarily assessed confirming the disassembling of the molecules in the biological milieu. Overall, some very interesting results emerged for these unconventional compounds from a mechanistic point of view., Competing Interests: Declaration of competing interest Tiziano Marzo reports financial support was provided by University of Pisa. Tiziano Marzo reports financial support was provided by Government of Italy. Diego La Mendola reports financial support was provided by University of Pisa. Iogann Tolbatov reports equipment, drugs, or supplies was provided by University of Burgundy. Iogann Tolbatov reports financial support was provided by European Union. Alessandro Marrone reports equipment, drugs, or supplies was provided by Interuniversity Consortium Cineca. Iogann Tolbatov reports financial support was provided by Council of the European Union. Tiziano Marzo reports equipment, drugs, or supplies was provided by University of Pisa. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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21. Non-Medical Applications of Inorganic Medicines. A Switch Based on Mechanistic Knowledge.
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Cirri D, Di Leo R, Chiaverini L, Tolbatov I, Marrone A, Messori L, Pratesi A, La Mendola D, and Marzo T
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- Catalysis, Humans, Palladium chemistry, Muramidase chemistry, Muramidase metabolism, Coordination Complexes chemistry, Arsenic chemistry, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology
- Abstract
Metals have been used in medicine for centuries. However, it was not until much later that the effects of inorganic drugs could be rationalized from a mechanistic point of view. Today, thanks to the technologies available, this approach has been functionally developed and implemented. It has been found that there is probably no single biological target for the pharmacological effects of most inorganic drugs. Herein, we present an overview of some integrated and multi-technique approaches to elucidate the molecular interactions underlying the biological effects of metallodrugs. On this premise, selected examples are used to illustrate how the information obtained on metal-based drugs and their respective mechanisms can become relevant for applications in fields other than medicine. For example, some well-known metallodrugs, which have been shown to bind specific amino acid residues of proteins, can be used to solve problems related to protein structure elucidation in crystallographic studies. Diruthenium tetraacetate can be used to catalyze the conversion of hydroxylamines to nitrones with a high selectivity when bound to lysozyme. Finally, a case study is presented in which an unprecedented palladium/arsenic-mediated catalytic cycle for nitrile hydration was discovered thanks to previous studies on the solution chemistry of the anticancer compound arsenoplatin-1 (AP-1)., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)
- Published
- 2024
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22. Description of a Non-Canonical AsPt Blue Species Originating from the Aerobic Oxidation of AP-1 in Aqueous Solution.
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Cirri D, Marzo T, Mastrorilli P, Petrelli V, Todisco S, De Giglio E, Gellini C, Ricci M, Pratesi A, and Messori L
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- Water chemistry, Solutions, Organoplatinum Compounds chemistry, Oxidation-Reduction
- Abstract
The peculiar behavior of arsenoplatin-1, ([Pt(µ-NHC(CH
3 )O)2 ClAs(OH)2 ], AP-1), in aqueous solution and the progressive appearance of a characteristic and intense blue color led us to carry out a more extensive investigation to determine the nature of this elusive chemical species, which we named "AsPt blue". A multi-technique approach was therefore implemented to describe the processes involved in the formation of AsPt blue, and some characteristic features of this intriguing species were revealed.- Published
- 2024
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23. Unveiling the mechanism of activation of the Te(IV) prodrug AS101. New chemical insights towards a better understanding of its medicinal properties.
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Chiaverini L, Tolbatov I, Marrone A, Marzo T, Biver T, and La Mendola D
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- Prodrugs pharmacology, Prodrugs chemistry
- Abstract
AS101 (Ammonium trichloro (dioxoethylene-O,O') tellurate) is an important hypervalent Te-based prodrug. Recently, we started a systematic investigation on AS101 with the aim to correlate its promising biological effects as a potent immunomodulator drug with multiple medicinal applications and its specific chemical properties. To date, a substantial agreement on the rapid conversion of the initial AS101 species into the corresponding TeOCl
3 - anion does exist, and this latter species is reputed as the pharmacologically active one. However, we realized that TeOCl3 - could quickly undergo further steps of conversion in an aqueous medium, eventually producing the TeO2 species. Using a mixed experimental and theoretical investigation approach, we characterized the conversion process leading to TeO2 occurring both in pure water and in reference buffers at physiological-like pH. Our findings may offer a valuable "chemical tool" for a better description, interpretation -and optimization- of the mechanism of action of AS101 and Te-based compounds. This might be a starting point for improved AS101-based medicinal application., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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24. Tyrosine kinase inhibitors (TKIs) for ovarian cancer treatment: from organic to inorganic chemotherapeutics towards selectivity-a perspective overview.
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Baglini E, Chiaverini L, Tolbatov I, Taliani S, Da Settimo F, La Mendola D, Barresi E, and Marzo T
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- Female, Humans, Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Antineoplastic Agents pharmacology, Ovarian Neoplasms drug therapy
- Abstract
Ovarian cancer (OC) is a lethal gynecologic cancer in industrialized countries. Treatments for OC include the surgical removal and chemotherapy. In the last decades, improvements have been made in the surgery technologies, drug combinations and administration protocols, and in diagnosis. However, mortality from OC is still high owing to recurrences and insurgence of drug resistance. Accordingly, it is urgent the development of novel agents capable to effectively target OC. In this respect, tyrosine kinase inhibitors (TKIs) may play an important role. Most of TKIs developed and tested so far are organic. However, owing to their chemical versatility, also metals can be exploited to design selective and potent TKIs. We provide a short and easy-to-read overview on the main organic TKIs with a summary of those that entered clinical trials. Additionally, we describe the potential of metal-based TKIs, focusing on this overlooked family of compounds that may significantly contribute towards the concept of precision-medicine., (© 2023. The Author(s).)
- Published
- 2024
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25. Oxaliplatin(IV) Prodrugs Functionalized with Gemcitabine and Capecitabine Induce Blockage of Colorectal Cancer Cell Growth-An Investigation of the Activation Mechanism and Their Nanoformulation.
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Marotta C, Cirri D, Kanavos I, Ronga L, Lobinski R, Funaioli T, Giacomelli C, Barresi E, Trincavelli ML, Marzo T, and Pratesi A
- Abstract
The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs. The design, synthesis, and characterization of two novel Pt(IV) prodrugs based on oxaliplatin bearing the anticancer drugs gemcitabine or capecitabine in the axial positions have been reported. These complexes were able to dissociate into their constituents to promote cell death and induce apoptosis and cell cycle blockade in a representative colorectal cancer cell model. Specifically, the complex bearing gemcitabine resulted in being the most active on the HCT116 colorectal cancer cell line with an IC
50 value of 0.49 ± 0.04. A pilot study on the encapsulation of these complexes in biocompatible PLGA-PEG nanoparticles is also included to confirm the retention of the pharmacological properties and cellular drug uptake, opening up to the possible delivery of the studied complexes through their nanoformulation.- Published
- 2024
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26. A complex bearing TSPO PIGA ligand coordinated to the [Au(PEt 3 )] + pharmacophore is highly cytotoxic against ovarian cancer cells.
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Chiaverini L, Baglini E, Mannelli M, Poggetti V, Da Settimo F, Taliani S, Gamberi T, Barresi E, La Mendola D, and Marzo T
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- Humans, Female, Auranofin, Pharmacophore, Ligands, Gold pharmacology, Gold chemistry, Thioredoxin-Disulfide Reductase, Cell Line, Tumor, Receptors, GABA, Antineoplastic Agents chemistry, Ovarian Neoplasms drug therapy
- Abstract
Auranofin ([1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato](triethylphosphine)-gold) is a leading gold-based drug clinically used to treat arthritis. In the last years, it entered various drug reprofiling programs, and it has been found promising against various forms of tumor, including ovarian cancer. Evidence showed as its antiproliferative profile mainly depends on the inhibition of thioredoxin reductase (TrxR), being this mitochondrial system its main target. In this context, we report here the synthesis and biological evaluation of a novel complex designed as auranofin analogue obtained through the conjugation of a phenylindolylglyoxylamide ligand (which belongs to the so-called PIGA TSPO ligand family) with the auranofin-derived cationic fragment [Au(PEt
3 )]+ . This complex is characterized by two parts. The phenylindolylglyoxylamide moiety, owing to its high affinity for TSPO (in the low nM range) should drive the compound to target mitochondria, whereas the [Au(PEt3 )]+ cation is the actual anticancer-active molecular fragment. Overall, we wanted to offer the proof-of-concept that by coupling PIGA ligands to anticancer gold active moieties, it is possible to preserve and even improve anticancer effects, opening the avenue to a reliable approach for targeted therapy., (© 2023. The Author(s).)- Published
- 2023
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27. An unprecedented palladium-arsenic catalytic cycle for nitriles hydration.
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Cirri D, Marzo T, and Pratesi A
- Abstract
An unprecedented palladium/arsenic-based catalytic cycle for the hydration of nitriles to the corresponding amides is here described. It occurs in exceptionally mild conditions such as neutral pH and moderate temperature (60°C). The versatility of this new catalytic cycle was tested on various nitriles from aliphatic to aromatic. Also, the effect of ring substitution with electron withdrawing and electron donating groups was investigated in the cases of aromatic nitriles, as well as the effect of potentially interferent functional groups such as hydroxy group or pyridinic nitrogen. Furthermore, a pilot study on the potential suitability of this approach for its scale-up is presented, revealing that the catalytic cycle could be potentially and quickly scaled up., Competing Interests: The topic reported in this paper is subjected to patent Deposit (inventors Damiano Cirri, Tiziano Marzo, Alessandro Pratesi) Number (Ministero delle Imprese e del Made in Italy, Italy, Università di Pisa): 102023000001458, 31 January 2023., (Copyright © 2023 Cirri, Marzo and Pratesi.)
- Published
- 2023
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28. Cisplatin binding to angiogenin protein: new molecular pathways and targets for the drug's anticancer activity.
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Ferraro G, Sanfilippo V, Chiaverini L, Satriano C, Marzo T, Merlino A, and La Mendola D
- Subjects
- Male, Humans, Cisplatin pharmacology, Ribonuclease, Pancreatic, Cell Line, Neoplasms, Antineoplastic Agents pharmacology
- Abstract
Cisplatin (CisPt), a platinum-based chemotherapeutic widely used in the treatment of various cancers, has multiple mechanisms of action, including nuclear DNA (nDNA) and mitochondrial DNA (mDNA) damage and cytoskeletal perturbations affecting, in turn, the membrane transporter activity. CisPt binding to proteins and enzymes may modulate its biochemical mechanism of action and is associated with cancer cell resistance to the drug. In this work, we investigate the interaction between cisplatin and angiogenin (Ang), a protein strongly expressed in many types of cancer and a potent angiogenic factor. The adduct formed upon reaction of CisPt with Ang (Ang@CisPt) was characterized by X-ray crystallography to evidence the exact platination site and by UV-visible (UV-vis) absorption and circular dichroism (CD) spectroscopies to shed light on any possible change in the protein conformation. Furthermore, high-resolution electrospray ionization (ESI) mass spectrometry was utilized to evaluate the Ang : CisPt stoichiometry of the Ang@CisPt adduct. The effect of the Ang@CisPt adduct on a prostate cancer cell line (PC-3) was tested by colorimetric assays in terms of cell viability, at both levels of nuclear and mitochondrial damage, and reactive oxygen species (ROS) production. Cellular imaging by laser scanning confocal microscopy (LSM) was utilized to scrutinize the cytoskeleton actin reorganization and the lysosome and mitochondria organelle perturbation. These studies highlight the possibility of new molecular pathways and targets for CisPt activity.
- Published
- 2023
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29. Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety.
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Ronga L, Tolbatov I, Giorgi E, Pisarek P, Enjalbal C, Marrone A, Tesauro D, Lobinski R, Marzo T, Cirri D, and Pratesi A
- Subjects
- Ligands, Gold chemistry, Magnetic Resonance Spectroscopy, Auranofin pharmacology, Auranofin chemistry, Antineoplastic Agents pharmacology
- Abstract
Auranofin, a gold(I)-based complex, is under clinical trials for application as an anticancer agent for the treatment of nonsmall-cell lung cancer and ovarian cancer. In the past years, different derivatives have been developed, modifying gold linear ligands in the search for new gold complexes endowed with a better pharmacological profile. Recently, a panel of four gold(I) complexes, inspired by the clinically established compound auranofin, was reported by our research group. As described, all compounds possess an [Au{P(OMe)
3 }]+ cationic moiety, in which the triethylphosphine of the parent compound auranofin was replaced with an oxygen-rich trimethylphosphite ligand. The gold(I) linear coordination geometry was complemented by Cl- , Br- , I- , and the auranofin-like thioglucose tetraacetate ligand. As previously reported, despite their close similarity to auranofin, the panel compounds exhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overall pharmacokinetic profiles. To get better insight into the P-Au strength and stability, an extensive study was carried out for relevant biological models, including three different vasopressin peptide analogues and cysteine, using31 P NMR and LC-ESI-MS. A DFT computational study was also carried out for a better understanding of the theoretical fundamentals of the disclosed differences with regard to triethylphosphine parent compounds.- Published
- 2023
- Full Text
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30. Inorganic Drugs as a Tool for Protein Structure Solving and Studies on Conformational Changes.
- Author
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Tolbatov I, Marrone A, Shepard W, Chiaverini L, Upadhyay Kahaly M, La Mendola D, Marzo T, and Ciccone L
- Subjects
- Proteins chemistry, Metals chemistry
- Abstract
Inorganic drugs are capable of tight interactions with proteins through coordination towards aminoacidic residues, and this feature is recognized as a key aspect for their pharmacological action. However, the "protein metalation process" is exploitable for solving the phase problem and structural resolution. In fact, the use of inorganic drugs bearing specific metal centers and ligands capable to drive the binding towards the desired portions of the protein target could represent a very intriguing and fruitful strategy. In this context, a theoretical approach may further contribute to solve protein structures and their refinement. Here, we delineate the main features of a reliable experimental-theoretical integrated approach, based on the use of metallodrugs, for protein structure solving., (© 2022 Wiley-VCH GmbH.)
- Published
- 2023
- Full Text
- View/download PDF
31. Pd-Based Hybrid Nanoparticles As Multimodal Theranostic Nanomedicine.
- Author
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Bellissima A, Cucci LM, Sanfilippo V, De Bonis A, Fiorenza R, Scirè S, Marzo T, Severi M, La Mendola D, Notarstefano V, Giorgini E, and Satriano C
- Subjects
- Male, Humans, Theranostic Nanomedicine methods, Palladium pharmacology, Palladium chemistry, Cisplatin chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemistry, Metal Nanoparticles therapeutic use, Metal Nanoparticles chemistry
- Abstract
A nanodelivery system based on palladium nanoparticles (PdNP) and cisplatin (CisPt) was developed by physisorption of the drug onto the PdNP synthesized via a green redox process, using d-glucose and polyvinylpyrrolidone (PVP) as reducing and stabilizing/capping agents, respectively. UV-vis analysis and H
2 -evolution measurements were carried out to prove the nanoparticles' capability to act as bimodal theranostic nanomedicine, i.e., having both plasmonic and photocatalytic properties. XPS, XRD, and TEM allowed light to be shed on the chemical composition and morphology of the PdNP. The analysis of the UV-visible spectra evidenced plasmonic peak changes for the hybrid nanoparticle-drug assembly (Pd@CisPt), which pointed to a significant interaction of CisPt with the NP surface. The drug loading was quantitatively estimated by ICP-OES measurements, while DLS and AFM confirmed the strong association of the drug with the nanoparticle surface. The test of SOD-like activity in a cell-free environment proved the maintenance of the antioxidant capability of PdNP also in the Pd@CisPt systems. Finally, Pd@CisPt tested in prostate cancer cells (PC-3 line) unveiled the antitumoral action of the developed nanomedicine, related to reactive oxygen species (ROS) generation, with a condition of protein misfolding/unfolding and DNA damage, as evidenced by cytotoxicity and MitoSOX assays, as well as Raman microspectroscopy, respectively. Cell imaging by confocal microscopy evidenced cellular uptake of the nanoparticles, as well as dynamic processes of copper ion accumulation at the level of subcellular compartments. Finally, cell migration studies upon treatment with Pd@CisPt evidenced a tunable response between the inhibitory effect of CisPt and the enhanced rate of cell migration for the metal NP alone, which pointed out the promising potential of the developed theranostic nanomedicine in tissue regeneration.- Published
- 2023
- Full Text
- View/download PDF
32. Neurotrophic Activity and Its Modulation by Zinc Ion of a Dimeric Peptide Mimicking the Brain-Derived Neurotrophic Factor N-Terminal Region.
- Author
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Russo L, Giacomelli C, Fortino M, Marzo T, Ferri G, Calvello M, Viegi A, Magrì A, Pratesi A, Pietropaolo A, Cardarelli F, Martini C, Rizzarelli E, Marchetti L, La Mendola D, and Trincavelli ML
- Subjects
- Brain-Derived Neurotrophic Factor, Zinc pharmacology
- Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin (NT) essential for neuronal development and synaptic plasticity. Dysregulation of BDNF signaling is implicated in different neurological disorders. The direct NT administration as therapeutics has revealed to be challenging. This has prompted the design of peptides mimicking different regions of the BDNF structure. Although loops 2 and 4 have been thoroughly investigated, less is known regarding the BDNF N-terminal region, which is involved in the selective recognition of the TrkB receptor. Herein, a dimeric form of the linear peptide encompassing the 1-12 residues of the BDNF N-terminal (d-bdnf) was synthesized. It demonstrated to act as an agonist promoting specific phosphorylation of TrkB and downstream ERK and AKT effectors. The ability to promote TrkB dimerization was investigated by advanced fluorescence microscopy and molecular dynamics (MD) simulations, finding activation modes shared with BDNF. Furthermore, d-bdnf was able to sustain neurite outgrowth and increase the expression of differentiation (NEFM, LAMC1) and polarization markers (MAP2, MAPT) demonstrating its neurotrophic activity. As TrkB activity is affected by zinc ions in the synaptic cleft, we first verified the ability of d-bdnf to coordinate zinc and then the effect of such complexation on its activity. The d-bdnf neurotrophic activity was reduced by zinc complexation, demonstrating the role of the latter in tuning the activity of the new peptido-mimetic. Taken together our data uncover the neurotrophic properties of a novel BDNF mimetic peptide and pave the way for future studies to understand the pharmacological basis of d-bdnf action and develop novel BDNF-based therapeutic strategies.
- Published
- 2022
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33. Medicinal Hypervalent Tellurium Prodrugs Bearing Different Ligands: A Comparative Study of the Chemical Profiles of AS101 and Its Halido Replaced Analogues.
- Author
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Chiaverini L, Cirri D, Tolbatov I, Corsi F, Piano I, Marrone A, Pratesi A, Marzo T, and La Mendola D
- Subjects
- Adjuvants, Immunologic therapeutic use, Ethylenes, Ligands, Tellurium, Prodrugs pharmacology
- Abstract
Ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a potent immunomodulator prodrug that, in recent years, entered various clinical trials and was tested for a variety of potential therapeutic applications. It has been demonstrated that AS101 quickly activates in aqueous milieu, producing TeOCl
3 - , which likely represents the pharmacologically active species. Here we report on the study of the activation process of AS101 and of two its analogues. After the synthesis and characterization of AS101 and its derivatives, we have carried out a comparative study through a combined experimental and computational analysis. Based on the obtained results, we describe here, for the first time, the detailed reaction that AS101 and its bromido- and iodido-replaced analogues undergo in presence of water, allowing the conversion of the original molecule to the likely true pharmacophore. Interestingly, moving down in the halogens' group we observed a higher tendency to react, attributable to the ligands' effect. The chemical and mechanistic implications of these meaningful differences are discussed.- Published
- 2022
- Full Text
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34. Anti-Staphylococcal Activity of the Auranofin Analogue Bearing Acetylcysteine in Place of the Thiosugar: An Experimental and Theoretical Investigation.
- Author
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Chiaverini L, Pratesi A, Cirri D, Nardinocchi A, Tolbatov I, Marrone A, Di Luca M, Marzo T, and La Mendola D
- Subjects
- Acetylcysteine pharmacology, Acetylcysteine therapeutic use, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Humans, Staphylococcus aureus, Auranofin chemistry, Auranofin pharmacology, Staphylococcal Infections drug therapy
- Abstract
Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt
3 ]+ . Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus , whereas it is about 20 times less effective against Staphylococcus epidermidis . Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt3 ]+ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH2 , corresponding to the tryptic C-terminal fragment (488-499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au-S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.- Published
- 2022
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35. Reactions of Arsenoplatin-1 with Protein Targets: A Combined Experimental and Theoretical Study.
- Author
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Tolbatov I, Cirri D, Tarchi M, Marzo T, Coletti C, Marrone A, Messori L, Re N, and Massai L
- Subjects
- Humans, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cisplatin chemistry, Cisplatin pharmacology, Density Functional Theory, Serum Albumin, Human chemistry, Serum Albumin, Human metabolism, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Myoglobin chemistry, Myoglobin metabolism
- Abstract
Arsenoplatin-1 (AP-1) is a dual-action anticancer metallodrug with a promising pharmacological profile that features the simultaneous presence of a cisplatin-like center and an arsenite center. We investigated its interactions with proteins through a joint experimental and theoretical approach. The reactivity of AP-1 with a variety of proteins, including carbonic anhydrase (CA), superoxide dismutase (SOD), myoglobin (Mb), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and human serum albumin (HSA), was analyzed by means of electrospray ionization mass spectrometry (ESI MS) measurements. In accordance with previous observations, ESI MS experiments revealed that the obtained metallodrug-protein adducts originated from the binding of the [(AP-1)-Cl]
+ fragment to accessible protein residues. Remarkably, in two cases, i.e., Mb and GAPDH, the formation of a bound metallic fragment that lacked the arsenic center was highlighted. The reactions of AP-1 with various nucleophiles side chains of neutral histidine, methionine, cysteine, and selenocysteine, in neutral form as well as cysteine and selenocysteine in anionic form, were subsequently analyzed through a computational approach. We found that the aquation of AP-1 is energetically disfavored, with a reaction free energy of +19.2 kcal/mol demonstrating that AP-1 presumably attacks its biological targets through the exchange of the chloride ligand. The theoretical analysis of thermodynamics and kinetics for the ligand-exchange processes of AP-1 with His, Met, Cys, Sec, Cys- , and Sec- side chain models unveils that only neutral histidine and deprotonated cysteine and selenocysteine are able to effectively replace the chloride ligand in AP-1.- Published
- 2022
- Full Text
- View/download PDF
36. Auranofin and its analogs as prospective agents for the treatment of colorectal cancer.
- Author
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Massai L, Cirri D, Marzo T, and Messori L
- Abstract
Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought. Platinum drugs, oxaliplatin in particular, were reported to produce some significant benefit in CRC treatment, triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs. Within this frame, gold compounds and, specifically, the established antiarthritic drug auranofin with its analogs, form a novel group of promising anticancer agents. Owing to its innovative mechanism of action and its favorable pharmacological profile, auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment, capable of overcoming resistance to platinum drugs. Some encouraging results in this direction have already been obtained. A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations. The perspectives of the research in this field are outlined., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2022.)
- Published
- 2022
- Full Text
- View/download PDF
37. Cancer Immunotherapy: An Overview of Small Molecules as Inhibitors of the Immune Checkpoint PD-1/PD-L1 (2015-2021).
- Author
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Baglini E, Salerno S, Barresi E, Marzo T, Settimo FD, and Taliani S
- Subjects
- B7-H1 Antigen antagonists & inhibitors, Humans, Immunotherapy, Ligands, Programmed Cell Death 1 Receptor antagonists & inhibitors, Antineoplastic Agents, Immunological therapeutic use, Neoplasms drug therapy
- Abstract
In 2018, James Allison and Tasuku Honjo received the Nobel Prize in physiology or medicine to discover tumor therapy by inhibition of negative immune regulation. Immunotherapy stimulates T-cells to fight cancer cells by blocking different immune checkpoint pathways. The interaction between programmed cell death 1 (PD-1) and its ligand PD-L1 (Programmed cell death ligand 1) is one of the main pathways. Of note, interfering with this pathway is already exploited in clinical cancer therapy, demonstrating that it is one of the key factors involved in the immune escape mechanism of cancer. The development of monoclonal antibodies (mAbs) that possess the ability to inhibit the interactions between PD-1/PD-L1 has radically made the difference in cancer immunotherapy. Yet, due to the many drawbacks of this therapy, the research shifted its efforts towards the development of novel small molecules. This may constitute hope and an arduous challenge in fighting cancer. This paper reviews the recent primary literature concerning the development of novel small molecules able to block the interaction between PD-1 and its ligand PD-L1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2022
- Full Text
- View/download PDF
38. Oxaliplatin inhibits angiogenin proliferative and cell migration effects in prostate cancer cells.
- Author
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Marzo T, Ferraro G, Cucci LM, Pratesi A, Hansson Ö, Satriano C, Merlino A, and La Mendola D
- Subjects
- Humans, Male, PC-3 Cells, Cell Movement drug effects, Cell Proliferation drug effects, Neoplasm Proteins metabolism, Oxaliplatin pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms metabolism, Ribonuclease, Pancreatic metabolism
- Abstract
Angiogenin (Ang) is a potent angiogenic protein that is overexpressed in many types of cancer at concentration values correlated to the tumor aggressiveness. Here, by means of an integrated multi-technique approach based on crystallographic, spectrometric and spectroscopic analyses, we demonstrate that the anti-cancer drug oxaliplatin efficiently binds angiogenin. Microscopy cellular studies, carried out on the prostate cancer cell (PC-3) line , show that oxaliplatin inhibits the angiogenin prompting effect on cell proliferation and migration, which are typical features of angiogenesis process. Overall, our findings point to angiogenin as a possible target of oxaliplatin, thus suggesting a potential novel mechanism for the antineoplastic activity of this platinum drug and opening the avenue to novel approaches in the combined anti-cancer anti-angiogenic therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
39. In Vitro Anti-SARS-CoV-2 Activity of Selected Metal Compounds and Potential Molecular Basis for Their Actions Based on Computational Study.
- Author
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Cirri D, Marzo T, Tolbatov I, Marrone A, Saladini F, Vicenti I, Dragoni F, Boccuto A, and Messori L
- Subjects
- 2,2'-Dipyridyl chemistry, 2,2'-Dipyridyl pharmacology, Animals, Antimony chemistry, Antiviral Agents chemistry, Cell Line, Chlorides chemistry, Chlorocebus aethiops, Drug Discovery, Humans, Indazoles chemistry, Organogold Compounds chemistry, Organometallic Compounds chemistry, Ruthenium Compounds chemistry, Vero Cells, 2,2'-Dipyridyl analogs & derivatives, Antimony pharmacology, Antiviral Agents pharmacology, Chlorides pharmacology, Indazoles pharmacology, Organogold Compounds pharmacology, Organometallic Compounds pharmacology, Ruthenium Compounds pharmacology, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl
3 ), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3 , and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.- Published
- 2021
- Full Text
- View/download PDF
40. Agricultural expansion and the ecological marginalization of forest-dependent people.
- Author
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Levers C, Romero-Muñoz A, Baumann M, De Marzo T, Fernández PD, Gasparri NI, Gavier-Pizarro GI, Waroux YLP, Piquer-Rodríguez M, Semper-Pascual A, and Kuemmerle T
- Subjects
- Humans, South America, Agriculture, Conservation of Natural Resources, Forests, Geographic Mapping, Social Marginalization
- Abstract
Agricultural expansion into subtropical and tropical forests causes major environmental damage, but its wider social impacts often remain hidden. Forest-dependent smallholders are particularly strongly impacted, as they crucially rely on forest resources, are typically poor, and often lack institutional support. Our goal was to assess forest-smallholder dynamics in relation to expanding commodity agriculture. Using high-resolution satellite images across the entire South American Gran Chaco, a global deforestation hotspot, we digitize individual forest-smallholder homesteads ( n = 23,954) and track their dynamics between 1985 and 2015. Using a Bayesian model, we estimate 28,125 homesteads in 1985 and show that forest smallholders occupy much larger forest areas (>45% of all Chaco forests) than commonly appreciated and increasingly come into conflict with expanding commodity agriculture (18% of homesteads disappeared; n = 5,053). Importantly, we demonstrate an increasing ecological marginalization of forest smallholders, including a substantial forest resource base loss in all Chaco countries and an increasing confinement to drier regions (Argentina and Bolivia) and less accessible regions (Bolivia). Our transferable and scalable methodology puts forest smallholders on the map and can help to uncover the land-use conflicts at play in many deforestation frontiers across the globe. Such knowledge is essential to inform policies aimed at sustainable land use and supply chains., Competing Interests: The authors declare no competing interest.
- Published
- 2021
- Full Text
- View/download PDF
41. Angiogenin and Copper Crossing in Wound Healing.
- Author
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Cucci LM, Satriano C, Marzo T, and La Mendola D
- Subjects
- Animals, Enzyme Activation, Gene Expression, Humans, Neovascularization, Physiologic genetics, Ribonuclease, Pancreatic chemistry, Ribonuclease, Pancreatic genetics, Structure-Activity Relationship, Copper metabolism, Ribonuclease, Pancreatic metabolism, Wound Healing physiology
- Abstract
Angiogenesis plays a key role in the wound healing process, involving the migration, growth, and differentiation of endothelial cells. Angiogenesis is controlled by a strict balance of different factors, and among these, the angiogenin protein plays a relevant role. Angiogenin is a secreted protein member of the ribonuclease superfamily that is taken up by cells and translocated to the nucleus when the process of blood vessel formation has to be promoted. However, the chemical signaling that activates the protein, normally present in the plasma, and the transport pathways through which the protein enters the cell are still largely unclear. Copper is also an angiogenic factor that regulates angiogenin expression and participates in the activation of common signaling pathways. The interaction between angiogenin and copper could be a relevant mechanism in regulating the formation of new blood vessel pathways and paving the way to the development of new drugs for chronic non-healing wounds.
- Published
- 2021
- Full Text
- View/download PDF
42. Reactivity of antitumor coinage metal-based N-heterocyclic carbene complexes with cysteine and selenocysteine protein sites.
- Author
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Tolbatov I, Marzo T, Coletti C, La Mendola D, Storchi L, Re N, and Marrone A
- Subjects
- Copper chemistry, Density Functional Theory, Gold chemistry, Ligands, Models, Chemical, Molecular Structure, Silver chemistry, Thermodynamics, Antineoplastic Agents chemistry, Coordination Complexes chemistry, Cysteine chemistry, Selenocysteine chemistry
- Abstract
The reaction of the antitumor M(I)-bis-N-heterocyclic carbene (M(I)-NHC) complexes, M = Cu, Ag, and Au, with their potential protein binding sites, i.e. cysteine and selenocysteine, was investigated by means of density functional theory approaches. Capped cysteine and selenocysteine were employed to better model the corresponding residues environment within peptide structures. By assuming the neutral or deprotonated form of the side chains of these amino acids and by considering the possible assistance of an external proton donor such as an adjacent acidic residue or the acidic component of the surrounding buffer environment, we devised five possible routes leading to the binding of the investigated M(I)-NHC scaffolds to these protein sites, reflecting their different location in the protein structure and exposure to the bulk. The targeting of either cysteine or selenocysteine in their neutral forms is a kinetically unfavored process, expected to be quite slow if observable at all at physiological temperature. On the other hand, the reaction with the deprotonated forms is much more favored, even though an external proton source is required to assist the protonation of the leaving carbene. Our calculations also show that all coinage metals are characterized by a similar reactivity toward the binding of cysteine and selenocysteine sites, although the Au(I) complex has significantly higher reaction and activation free energies compared to Cu(I) and Ag(I)., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
43. Peptides Derived from Angiogenin Regulate Cellular Copper Uptake.
- Author
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Tabbì G, Cucci LM, Pinzino C, Munzone A, Marzo T, Pizzanelli S, Satriano C, Magrì A, and La Mendola D
- Subjects
- Cell Line, Tumor, Electron Spin Resonance Spectroscopy, Escherichia coli, Humans, Ribonuclease, Pancreatic metabolism, Copper metabolism, Ribonuclease, Pancreatic chemistry
- Abstract
The angiogenin protein (ANG) is one of the most potent endogenous angiogenic factors. In this work we characterized by means of potentiometric, spectroscopic and voltammetric techniques, the copper complex species formed with peptide fragments derived from the N-terminal domain of the protein, encompassing the sequence 1-17 and having free amino, Ang1-17, or acetylated N-terminus group, AcAng1-17, so to explore the role of amino group in metal binding and cellular copper uptake. The obtained data show that amino group is the main copper anchoring site for Ang1-17. The affinity constant values, metal coordination geometry and complexes redox-potentials strongly depend, for both peptides, on the number of copper equivalents added. Confocal laser scanning microscope analysis on neuroblastoma cells showed that in the presence of one equivalent of copper ion, the free amino Ang1-17 increases cellular copper uptake while the acetylated AcAng1-17 strongly decreases the intracellular metal level. The activity of peptides was also compared to that of the protein normally present in the plasma (wtANG) as well as to the recombinant form (rANG) most commonly used in literature experiments. The two protein isoforms bind copper ions but with a different coordination environment. Confocal laser scanning microscope data showed that the wtANG induces a strong increase in intracellular copper compared to control while the rANG decreases the copper signal inside cells. These data demonstrate the relevance of copper complexes' geometry to modulate peptides' activity and show that wtANG, normally present in the plasma, can affect cellular copper uptake.
- Published
- 2021
- Full Text
- View/download PDF
44. Anticancer effects against colorectal cancer models of chloro(triethylphosphine)gold(I) encapsulated in PLGA-PEG nanoparticles.
- Author
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Menconi A, Marzo T, Massai L, Pratesi A, Severi M, Petroni G, Antonuzzo L, Messori L, Pillozzi S, and Cirri D
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Capsules, Cell Cycle drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Drug Screening Assays, Antitumor, Humans, Organogold Compounds chemical synthesis, Organogold Compounds chemistry, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Colorectal Neoplasms drug therapy, Nanoparticles chemistry, Organogold Compounds pharmacology, Polyesters chemistry, Polyethylene Glycols chemistry
- Abstract
Chloro(triethylphosphine)gold(I), (Et
3 PAuCl hereafter), is an Auranofin (AF)-related compound showing very similar biological and pharmacological properties. Like AF, Et3 PAuCl exhibits potent antiproliferative properties in vitro toward a variety of cancer cell lines and is a promising anticancer drug candidate. We wondered whether Et3 PAuCl encapsulation might lead to an improved pharmacological profile also considering the likely reduction of unwanted side-reactions that are responsible for adverse effects and for drug inactivation. Et3 PAuCl was encapsulated in biocompatible PLGA-PEG nanoparticles (NPs) and the new formulation evaluated in colorectal HCT-116 cancer cells in comparison to the free gold complex. Notably, encapsulated Et3 PAuCl (nano-Et3 PAuCl hereafter) mostly retains the cellular properties of the free gold complex and elicits even greater cytotoxic effects in colorectal cancer (CRC) cells, mediated by apoptosis and autophagy. Moreover, a remarkable inhibition of two crucial signaling pathways, i.e. ERK and AKT, by nano-Et3 PAuCl, was clearly documented. The implications of these findings are discussed., (© 2021. The Author(s).)- Published
- 2021
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- View/download PDF
45. Two mixed valence diruthenium(II,III) isomeric complexes show different anticancer properties.
- Author
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Barresi E, Tolbatov I, Marzo T, Zappelli E, Marrone A, Re N, Pratesi A, Martini C, Taliani S, Da Settimo F, and La Mendola D
- Abstract
In this paper it is demonstrated that the nature of the ligands of two Ru2(ii,iii) paddlewheel complexes dramatically affects the overall anticancer properties in cells. Herein, the complex [Ru2(EB776)4Cl] was found to be more active against a glioblastoma model with respect to its isomer [Ru2(EB106)4Cl]. These different effects depend on the steric hindrance, on the allowed conformations of the complexes and on the presence of hydrophilic regions in [Ru2(EB776)4Cl], which overall lead to a lower "steric protection".
- Published
- 2021
- Full Text
- View/download PDF
46. Strategies for the Improvement of Metal-Based Chemotherapeutic Treatments.
- Author
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Cirri D, Bartoli F, Pratesi A, Baglini E, Barresi E, and Marzo T
- Abstract
This article provides an overview of the various research approaches we have explored in recent years to improve metal-based agents for cancer or infection treatments. Although cisplatin, carboplatin, and oxaliplatin remain the cornerstones in tumor chemotherapy, the discovery and approval of novel inorganic anticancer drugs is a very slow process. Analogously, although a few promising inorganic drugs have found clinical application against parasitic or bacterial infections, their use remains relatively limited. Moreover, the discovery process is often affected by small therapeutic enhancements that are not attractive for the pharmaceutical industry. However, the availability of increasing mechanistic information for the modes of action of established inorganic drugs is fueling the exploration of various approaches for developing effective inorganic chemotherapy agents. Through a series of examples, some from our own research experience, we focus our attention on a number of promising strategies, including (1) drug repurposing, (2) the simple modification of the chemical structures of approved metal-based drugs, (3) testing novel drug combinations, and (4) newly synthesized complexes coupling different anticancer drugs. Accordingly, we aim to suggest and summarize a series of reliable approaches that are exploitable for the development of improved and innovative treatments.
- Published
- 2021
- Full Text
- View/download PDF
47. Ruthenium(II) 1,4,7-trithiacyclononane complexes of curcumin and bisdemethoxycurcumin: Synthesis, characterization, and biological activity.
- Author
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Pettinari R, Marchetti F, Tombesi A, Duan F, Zhou L, Messori L, Giacomelli C, Marchetti L, Trincavelli ML, Marzo T, La Mendola D, Balducci G, and Alessio E
- Subjects
- Cell Survival, Coordination Complexes chemical synthesis, Crystallography, X-Ray, Humans, Models, Molecular, Neoplasms pathology, Tumor Cells, Cultured, Alkanes chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Coordination Complexes pharmacology, Curcumin chemistry, Neoplasms drug therapy, Ruthenium chemistry, Sulfur Compounds chemistry
- Abstract
Two cationic ruthenium(II) 1,4,7-trithiacyclononane ([9]aneS
3 ) complexes of curcumin (curcH) and bisdemethoxycurcumin (bdcurcH), namely [Ru(curc)(dmso-S)([9]aneS3 )]Cl (1) and [Ru(bdcurc)(dmso-S)([9]aneS3 )]Cl (2) were prepared from the [RuCl2 (dmso-S)([9]-aneS3 )] precursor and structurally characterized, both in solution and in the solid state by X-ray crystallography. The corresponding PTA complexes [Ru(curc)(PTA)([9]aneS3 )]Cl (3) and [Ru(bdcurc)(PTA)([9]aneS3 )]Cl (4) have been also synthesized and characterized (PTA = 1,3,5-triaza-7-phosphaadamantane). Bioinorganic studies relying on mass spectrometry were performed on complexes 1-4 to assess their interactions with the model protein lysozyme. Overall, a rather limited reactivity with lysozyme was highlighted accompanied by a modest cytotoxic potency against three representative cancer cell lines. The moderate pharmacological activity is likely connected to the relatively high stability of these complexes., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
48. Development of Effective Antibacterial Treatment: Lessons from the Past and Novel Approaches.
- Author
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Di Luca M and Marzo T
- Abstract
In the last three decades, the appearance and rapid diffusion of antibiotic-resistant bacterial strains have been observed [...].
- Published
- 2021
- Full Text
- View/download PDF
49. The first step of arsenoplatin-1 aggregation in solution unveiled by solving the crystal structure of its protein adduct.
- Author
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Ferraro G, Cirri D, Marzo T, Pratesi A, Messori L, and Merlino A
- Subjects
- Arsenic Trioxide chemistry, Cisplatin chemistry, Molecular Structure, Protein Binding, Solutions, Antineoplastic Agents chemistry, Arsenic Trioxide analogs & derivatives, Arsenites chemistry, Cisplatin analogs & derivatives, Coordination Complexes chemistry, Muramidase chemistry, Platinum chemistry
- Abstract
Arsenoplatin-1 (AP-1) is an innovative dual-action anticancer agent that contains a platinum(ii) center coordinated to an arsenous acid moiety. We found that AP-1 spontaneously aggregates in aqueous solutions generating oligomeric species of increasing length. Afterward, we succeeded in solving the crystal structure of the adduct formed between the model protein lysozyme and an early AP-1 oligomer that turned out to be a trimer. Remarkably, this crystal structure traps an early stage of AP-1 aggregation offering detailed insight into the molecular process of the oligomer's growth.
- Published
- 2021
- Full Text
- View/download PDF
50. The Effects on Angiogenesis of Relevant Inorganic Chemotherapeutics.
- Author
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Marzo T and La Mendola D
- Subjects
- Angiogenesis Inhibitors chemistry, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Coordination Complexes chemistry, Humans, Metals, Heavy chemistry, Neoplasms metabolism, Neoplasms pathology, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Coordination Complexes pharmacology, Metals, Heavy pharmacology, Neoplasms drug therapy, Neovascularization, Pathologic drug therapy
- Abstract
Angiogenesis is a key process allowing the formation of blood vessels. It is crucial for all the tissues and organs, ensuring their function and growth. Angiogenesis is finely controlled by several mechanisms involving complex interactions between pro- or antiangiogenic factors, and an imbalance in this control chain may result in pathological conditions. Metals as copper, zinc and iron cover an essential role in regulating angiogenesis, thus therapies having physiological metals as target have been proposed. In addition, some complexes of heavier metal ions (e.g., Pt, Au, Ru) are currently used as established or experimental anticancer agents targeting genomic or non-genomic targets. These molecules may affect the angiogenic mechanisms determining different effects that have been only poorly and non-systematically investigated so far. Accordingly, in this review article, we aim to recapitulate the impact on the angiogenic process of some reference anticancer drugs, and how it is connected to the overall pharmacological effects. In addition, we highlight how the activity of these drugs can be related to the role of biological essential metal ions. Overall, this may allow a deeper description and understanding of the antineoplastic activity of both approved or experimental metal complexes, providing important insights for the synthesis of new inorganic drugs able to overcome resistance and recurrence phenomena., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2021
- Full Text
- View/download PDF
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