Nampt inhibition by (E)-Daporinad (FK866) leads to a significant reduction in NAD+ levels intracellularly, selectively killing multiple myeloma (MM) cells. The cell death induced by (E)-Daporinad is linked to the inhibition of Nampt activity, not its protein expression. MM cells, having higher baseline NAD+ levels compared to normal peripheral blood mononuclear cells (PBMCs), are more susceptible to (E)-Daporinad. Additionally, (E)-Daporinad neutralizes the survival benefits that the bone marrow microenvironment confers on MM cells[1]. (E)-Daporinad (FK866) inhibits the increase in intracellular calcium ([Ca2+].i) that is typically induced by various mitogens and decreases the calcium content of thapsigargin-responsive calcium stores in Jurkat cells and activated peripheral blood lymphocytes (PBLs). However, it does not affect the calcium content in Bcl2-overexpressing Jurkat cells[2]. The inhibition of NAMPT by (E)-Daporinad (FK866), or SIRT by nicotinamide, reduces cell proliferation and induces cell death in 293T cells. This effect involves the p53 acetylation pathway, highlighting a critical regulatory mechanism in cell survival and death[3].
体内研究
In vivo, (E)-Daporinad (FK866) administered at 30 mg/kg intraperitoneally reduces tumor burden in CB17-SCID mice. In these mice, tumor tissues show significant reductions in ERK phosphorylation and increased proteolytic cleavage of LC3, indicating both signaling inhibition and autophagic activity[1].
体外研究
Nampt inhibition by (E)-Daporinad (FK866) leads to a significant reduction in NAD+ levels intracellularly, selectively killing multiple myeloma (MM) cells. The cell death induced by (E)-Daporinad is linked to the inhibition of Nampt activity, not its protein expression. MM cells, having higher baseline NAD+ levels compared to normal peripheral blood mononuclear cells (PBMCs), are more susceptible to (E)-Daporinad. Additionally, (E)-Daporinad neutralizes the survival benefits that the bone marrow microenvironment confers on MM cells[1].
(E)-Daporinad (FK866) inhibits the increase in intracellular calcium ([Ca2+].i) that is typically induced by various mitogens and decreases the calcium content of thapsigargin-responsive calcium stores in Jurkat cells and activated peripheral blood lymphocytes (PBLs). However, it does not affect the calcium content in Bcl2-overexpressing Jurkat cells[2].
The inhibition of NAMPT by (E)-Daporinad (FK866), or SIRT by nicotinamide, reduces cell proliferation and induces cell death in 293T cells. This effect involves the p53 acetylation pathway, highlighting a critical regulatory mechanism in cell survival and death[3].
(E)-Daporinad/达珀利奈 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human monocyte-derived macrophages (MDMs)
10 μM
20 hours
To investigate the effect of FK866 on KP enzymes and metabolites, results showed that FK866 significantly increased the levels of KP enzymes and metabolites.
Nat Immunol. 2019 Jan;20(1):50-63.
(E)-Daporinad/达珀利奈 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NMRI athymic mice
Xenograft model
Intraperitoneal injection
15-20 mg/kg
Twice daily for 14 days
To evaluate the therapeutic effect of APO866 on HCT-116 and HCT-116/APO866 xenograft tumors
Antiproliferative activity against human A2780 cells after 72 hrs by sulforhodamine B assay, IC50=1 nM
24405419
human A431 cells
Cytotoxic assay
Cytotoxicity against human A431 cells by clonogenic assay, IC50=6.1 nM
24164086
human A549 cells
Cytotoxic assay
6 days
Cytotoxicity against human A549 cells after 6 days by SRB assay, IC50=0.16 μM
21330015
human HCT116 cells
Cytotoxic assay
72 h
Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by WST-1 assay, IC50=10.9 nM
24164086
human HCT116 cells
Cytotoxic assay
6 days
Cytotoxicity against human HCT116 cells after 6 days by SRB assay, IC50=0.16 μM
21330015
human HepG2 cells
Function assay
1 h
Inhibition of NAMPT in human HepG2 cells using [14C]-nicotinamide/PRPP as substrate assessed as formation of [14C]-nicotinamide mononucleotide after 1 hr by liquid scintillation counting analysis, IC50=2.2 nM
24164086
human HT1080 cells
Cytotoxic assay
6 days
Cytotoxicity against human HT1080 cells after 6 days by SRB assay, IC50=0.16 μM
21330015
human K562 cells
Cytotoxic assay
96 h
Cytotoxicity against human K562 cells after 96 hrs by MTT assay, IC50=7.2 nM
23679915
human MCF7 cells
10 μM
Function assay
6 days
Antitumor activity against human MCF7 cells at 10 uM after 6 days by SRB assay, IC50=0.68 μM
21330015
human MCF-7 cells
Cytotoxic assay
72 h
Cytotoxicity against human MCF-7 cells assessed as growth inhibition after 72 hrs by WST-1 assay, IC50=7.4 nM
24164086
human NYH cells
Cytotoxic assay
3 weeks
Cytotoxicity against human NYH cells after 3 weeks by clonogenic survival assay, IC50=1.5 nM
23679915
human PC3 cells
Cytotoxic assay
Cytotoxicity against human PC3 cells by clonogenic assay, IC50=3.8 nM
24164086
human SH-SY5Y cells
Cytotoxic assay
Cytotoxicity against human SH-SY5Y cells assessed as reduction of total cellular NAD(P) level, IC50=0.5 nM
19961183
human SKOV3 cells
Cytotoxic assay
Cytotoxicity against human SKOV3 cells by clonogenic assay, IC50=211 nM
24164086
human SNU638 cells
Cytotoxic assay
6 days
Cytotoxicity against human SNU638 cells after 6 days by SRB assay, IC50=0.16 μM
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