Nicotinamide phosphoribosyltransferase inhibitor APO866 induces C6 glioblastoma cell death via autophagy.

Abstract

APO866 is a potent inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), and inhibits nicotinamide adenine dinucleotide (NAD) synthesis. Our previous study showed that APO866 inhibits the proliferation of C6 glioblastoma cells, but failed to induce apoptosis. Since APO866 inhibits cellular metabolism and such metabolic stress is closely related with autophagy, thus we determined whether APO866 can induce autophagy in C6 glioblastoma cells and whether the autophagy induced by APO866 is pro-death or pro-survival. Using LC3 immunofluorescence imaging and transmission electron microscopy detection, we found that APO866 at 1-100 nM induced autophagy in C6 glioblastoma cells. APO866 at 1 nM mainly induced initial autophagic vacuoles. Whereas APO866 at 100 nM induced degrading autophagic vacuoles, as well as induced nuclei malformation and mitochondria swelling. In addition, APO866 concentration-dependently decreased the cell viability of C6 glioblastoma cells, and this effect was attenuated by autophagy inhibitors, including 3-methyladenine and LY294002. APO866 concentration-dependently decreased intracellular NAD level. Interestingly, APO866 at 1 nM slightly decreased intracellular NAD level, but dramatically increased autophagy-positive cells. The dramatical cell viability decreasing required the decreasing of intracellular NAD level to a very low threshold. Thus, our results indicated that APO866 induced pro-death autophagy in C6 glioblastoma cells by decreasing intracellular NAD, and low concentration of APO866 can be used as an autophagy inducer in autophagic-death sensitive glioblastoma.

• Authors: Ping Yang, Lu Zhang, Qiao-Juan Shi, Yun-Bi Lu, Ming Wu, Er-Qing Wei, Wei-Ping Zhang
• Journal: Die Pharmazie (Pharmazie) Vol. 70 Issue 10 Pg. 650-5 (Oct 2015) ISSN: 0031-7144 [Print] Germany
• PMID: 26601421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acrylamides
• Enzyme Inhibitors
• N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
• Piperidines
• NAD
• Nicotinamide Phosphoribosyltransferase

Topics

• Acrylamides (pharmacology)
• Animals
• Autophagy (drug effects)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Glioblastoma (drug therapy, pathology)
• NAD (metabolism)
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors)
• Piperidines (pharmacology)
• Rats
• Vacuoles (drug effects)