TY - JOUR T1 - Reciprocal potentiation of the antitumoral activities of FK866, an inhibitor of nicotinamide phosphoribosyltransferase, and etoposide or cisplatin in neuroblastoma cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.184630 SP - jpet.111.184630 AU - Cristina Travelli AU - Valentina Drago AU - Elena Maldi AU - Nina Kaludercic AU - Ubaldina Galli AU - Renzo Boldorini AU - Fabio Di Lisa AU - Gian Cesare Tron AU - Pier Luigi Canonico AU - Armando A Genazzani Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/06/17/jpet.111.184630.abstract N2 - Nicotinamide adenine dinucleotide (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 emerged recently. 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 (NAMPT) has been shown to be an effective treatment in a number of preclinical studies, and two lead molecules (FK866 and CHS828) 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 ATG7. Autophagy, in this model, appears 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 co-treatment of cells with ineffective concentrations of FK866 (1nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment while the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, co-treatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion. ER -