FK866 (APO866)

FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase) with IC50 values ranging between 0.09nM and 27.2nM [1].

NAD plays a vital role in numerous biochemical and biologic processes. Targeting NAD synthesis is thought to be a selective manner to kill cancer cells since cancer cells have a higher rate of NAD turnover compared with normal cells. In the in vitro MTT assay using a panel of 41 human hematologic cancer

cell lines, most cancer cells are sensitive to low concentrations of FK866. Among these cancer cells, AML cells are most sensitive. FK866 is shown selective to human hematologic malignant cells and the normal human HPCs are resistant to FK866 treatment. It is found that FK866 induces cell death in a caspase-independent pathway but in a dose-dependent manner to induce mitochondrial membrane depolarization. Additionally, FK866 induces cell autophagy dependenting on de novo protein synthesis. FK866 also reduces ATP levels in ML-2 cells due to the inhibition of NAD synthesis. The antitumor efficacy of FK866 is also shown in the in vivo models. FK866 significantly prevents tumor growth both in mice xenografted subcutaneously with AML-M4 and Namalwa cells. Furthermore, FK866 clears tumor cells to below detectable levels and results in 80% survival for a long-term [1].

References:
[1] Nahimana A, Attinger A, Aubry D, Greaney P, Ireson C, Thougaard AV, Tjørnelund J, Dawson KM, Dupuis M, Duchosal MA. The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies. Blood. 2009 Apr 2;113(14):3276-86.

NAMPT protects against 6-hydroxydopamine-induced neurotoxicity in PC12 cells through modulating SIRT1 activity.[Pubmed:27035562]

Mol Med Rep. 2016 May;13(5):4058-64.

Parkinson's disease (PD) is the second most common progressive neurodegenerative movement disorder. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first ratelimiting step in the nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in mammals, is a substrate for NAD+dependent enzymes, such as sirtuin 1 (SIRT1), and contributes to cell fate decisions. However, the role of NAMPT in PD has remained to be fully elucidated. In the present study, PC12 cells were treated with the neurotoxin 6-hydroxydopamine (6OHDA) to establish an in vitro model of PD, following which an obvious inhibitory effect on the levels of NAMPT and NAD+ as well as the NAD+/NADH ratio was detected. In addition, preincubation with FK866, a highly specific NAMPT inhibitor, enhanced the inhibitory effects of 6OHDA on the viability of PC12, while preincubation with nicotinamide mononucleotide (NMN), am enzymatic product of NAMPT, had the opposite effect. Furthermore, it was revealed that NMN markedly attenuated 6OHDAinduced decreases in superoxide dismutase activity and glutathione levels, as well as 6OHDAinduced increases in malondialdehyde and lactate dehydrogenase in PC12 cells. Furthermore, 6OHDA significantly reduced SIRT1 activity in PC12 cells, which was inhibited by NMN. The pharmacological activator resveratrol also significantly inhibited 6OHDAmediated decreases in PC12 cell viability while reversing 6OHDAinduced decreases in SIRT1 levels. The results of the present study suggested that NMT protected against 6OHDAinduced decreases in PC12 cell viability, and that SIRT1 activation had a role in this process. Treatment with NMN to activate SIRT1 may represent a novel therapeutic strategy for treating PD.

Nampt Expression Decreases Age-Related Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Sirt1.[Pubmed:28125705]

PLoS One. 2017 Jan 26;12(1):e0170930.

Senescence restricts the development of applications involving mesenchymal stem cells (MSCs) in research fields, such as tissue engineering, and stem cell therapeutic strategies. Understanding the mechanisms underlying natural aging processes may contribute to the development of novel approaches to preventing age-related diseases or slowing individual aging processes. Nampt is a rate-limiting NAD biosynthetic enzyme that plays critical roles in energy metabolism, cell senescence and maintaining life spans. However, it remains unknown whether Nampt influences stem cell senescence. In this study, the function of Nampt was investigated using a rat model of natural aging. Our data show that Nampt expression was significantly lower in MSCs obtained from aged rats than in those obtained from young rats during physiological aging. Reducing the level of Nampt in aged MSCs resulted in lower intracellular concentrations of NAD+ and downregulated Sirt1 expression and activity. After the Nampt inhibitor FK866 was added, young MSCs were induced to become aged cells. The enhanced senescence was correlated with NAD+ depletion and Sirt1 activity attenuation. In addition, Nampt overexpression attenuated cell senescence in aged MSCs. Our findings provide a new explanation for the mechanisms underlying stem cell senescence and a novel target for delaying stem cell senescence and preventing and treating age-related diseases.

Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway.[Pubmed:28097126]

Biomed Res Int. 2016;2016:1450843.

Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100 muM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.

Regulation of the Nampt-mediated NAD salvage pathway and its therapeutic implications in pancreatic cancer.[Pubmed:27233476]

Cancer Lett. 2016 Aug 28;379(1):1-11.

Nicotinamide adenine dinucleotide (NAD) is a crucial cofactor for the redox reactions in the metabolic pathways of cancer cells that have elevated aerobic glycolysis (Warburg effect). Cancer cells are reported to rely on NAD recycling and inhibition of the NAD salvage pathway causes metabolic collapse and cell death. However, the underlying regulatory mechanisms and clinical implications for the NAD salvage pathway in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study showed that the expression of Nampt, the rate-limiting enzyme of the NAD salvage pathway, was significantly increased in PDAC cells and PDAC tissues. Additionally, inhibition of Nampt impaired tumor growth in vitro and tumorigenesis in vivo, which was accompanied by a decreased cellular NAD level and glycolytic activity. Mechanistically, the Nampt expression was independent of Kras and p16 status, but it was directly regulated by miR-206, which was inversely correlated with the expression of Nampt in PDAC tissues. Importantly, pharmacological inhibition of Nampt by its inhibitor, FK866, significantly enhanced the antitumor activity of gemcitabine in PDAC cells and in orthotopic xenograft mouse models. In conclusion, the present study revealed a novel regulatory mechanism for Nampt in PDAC and suggested that Nampt inhibition may override gemcitabine resistance by decreasing the NAD level and suppressing glycolytic activity, warranting further clinical investigation for pancreatic cancer treatment.

(E)-Daporinad (FK866) is an effective inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase; Nampt) with an IC50 of 0.09 nM.

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