title: Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.
abstract: Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors.
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and CEBR, University of Genova, 16132 Genova, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sociali
authors.affiliation: Laboratorio di Oncologia Istituto G. Gaslini, 16147 Genova, Italy.
authors.forename: Lizzia
authors.initials: L
authors.lastname: Raffaghello
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and CEBR, University of Genova, 16132 Genova, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Magnone
authors.affiliation: Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zamporlini
authors.affiliation: Animal Facility, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and CEBR, University of Genova, 16132 Genova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Sturla
authors.affiliation: Laboratorio di Oncologia Istituto G. Gaslini, 16147 Genova, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and CEBR, University of Genova, 16132 Genova, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Vigliarolo
authors.affiliation: Service and Central Laboratory of Hematology, University Hospital of Lausanne, 1011-CHUV, Lausanne, Switzerland.
authors.forename: Aimable
authors.initials: A
authors.lastname: Nahimana
authors.affiliation: Department of Internal Medicine, University of Genova, 16132 Genova, Italy.|IRCCS A.O.U. San Martino IST, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.affiliation: Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Raffaelli
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and CEBR, University of Genova, 16132 Genova, Italy.
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000178:Acrylamides / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000096:biosynthesis; D009537:Nicotinamide Mononucleotide / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000628:therapy*; D010880:Piperidines / Q000494:pharmacology*; D011726:Pyridinium Compounds; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000178:Acrylamides; D016207:Cytokines; D058851:GPI-Linked Proteins; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D011726:Pyridinium Compounds; D034741:RNA, Small Interfering; C018613:nicotinamide-beta-riboside; D009243:NAD; D009537:Nicotinamide Mononucleotide; D009536:Niacinamide; D000255:Adenosine Triphosphate; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C002630:alpha,beta-methyleneadenosine 5'-triphosphate
keywords: CD73; NAD+; NAMPT; ovarian cancer