title: Reciprocal potentiation of the antitumoral activities of FK866, an inhibitor of nicotinamide phosphoribosyltransferase, and etoposide or cisplatin in neuroblastoma cells.
abstract: NAD is an essential coenzyme involved in numerous metabolic pathways. Its principal role is in redox reactions, and as such it is not heavily "consumed" by cells. Yet a number of signaling pathways that bring about its consumption have recently emerged. This has brought about the hypothesis that the enzymes that lead to its biosynthesis may be targets for anticancer therapy. In particular, inhibition of the enzyme nicotinamide phosphoribosyl transferase has been shown to be an effective treatment in a number of preclinical studies, and two lead molecules [N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2E-propenamide (FK866) and (E)-1-[6-(4-chlorophenoxy)hexyl]-2-cyano-3-(pyridin-4-yl)guanidine (CHS 828)] have now entered preclinical trials. Yet, the full potential of these drugs is still unclear. In the present study we have investigated the role of FK866 in neuroblastoma cell lines. We now confirm that FK866 alone in neuroblastoma cells induces autophagy, and its effects are potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagy-related protein 7. Autophagy, in this model, seems to be crucial for FK866-induced cell death. On the other hand, a striking potentiation of the effects of cisplatin and etoposide is given by cotreatment of cells with ineffective concentrations of FK866 (1 nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment, whereas the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, cotreatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion.
authors.affiliation: Department of Chemical, Food, Pharmaceutical, and Pharmacological Sciences, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Travelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Drago
authors.forename: Elena
authors.initials: E
authors.lastname: Maldi
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.forename: Ubaldina
authors.initials: U
authors.lastname: Galli
authors.forename: Renzo
authors.initials: R
authors.lastname: Boldorini
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Lisa
authors.forename: Gian Cesare
authors.initials: GC
authors.lastname: Tron
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D000178:Acrylamides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D017304:Annexin A5 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D020552:Comet Assay; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D044764:Ubiquitin-Activating Enzymes / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000178:Acrylamides; D017304:Annexin A5; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D005047:Etoposide; C031080:3-methyladenosine; D002738:Chloroquine; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D054409:Nicotinamide Phosphoribosyltransferase; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000241:Adenosine; D002945:Cisplatin