Identification of Piperlongumine as Potent Inhibitor of Necroptosis

by Selleckchem | Jun 14 2023

Purpose: Excessive necroptosis contributes to the pathogenesis of several inflammatory and neurodegenerative diseases. Here, using a high-throughput screening approach, we investigated the anti-necroptosis effects of piperlongumine, an alkaloid isolated from the long pepper plant, in vitro and in a mouse model of systemic inflammatory response syndrome (SIRS).

Methods: A natural compound library was screened for anti-necroptosis effects in cellular. The underlying mechanism of action of the top candidate piperlongumine was explored by quantifying the necroptosis marker phosphorylated receptor-interacting protein kinase 1 (p-RIPK1) by Western blotting. The anti-inflammatory effect of piperlongumine was assessed in a tumor necrosis factor α (TNFα)-induced SIRS model in mice.

Results: Among the compounds investigated, piperlongumine significantly rescued cell viability. The half maximal effective concentration (EC50) of piperlongumine for inhibiting necroptosis was 0.47 μM in HT-29 cells, 6.41 μM in FADD-deficient Jurkat cells, and 2.33 µM in CCRF-CEM cells, while the half maximal inhibitory concentration (IC50) was 95.4 µM in HT-29 cells, 93.02 µM in FADD-deficient Jurkat cells, and 161.1 µM in CCRF-CEM cells. Piperlongumine also significantly inhibited TNFα-induced intracellular RIPK1 Ser166 phosphorylation in cell lines and significantly prevented decreases in body temperature and improved survival in SIRS mice.

Conclusion: As a potent necroptosis inhibitor, piperlongumine prevents phosphorylation of RIPK1 at its activation residue Ser166. Piperlongumine thus potently inhibits necroptosis at concentrations safe enough for human cells in vitro and inhibits TNFα-induced SIRS in mice. Piperlongumine has potential clinical translational value for the treatment of the spectrum of diseases associated with necroptosis, including SIRS.

Comments:

The given passage describes a study that investigated the effects of piperlongumine, an alkaloid derived from the long pepper plant, on necroptosis, a form of programmed cell death associated with various inflammatory and neurodegenerative diseases. The researchers conducted a high-throughput screening of a natural compound library to identify potential anti-necroptosis compounds and found that piperlongumine showed significant rescue of cell viability.

The researchers further explored the mechanism of action of piperlongumine by examining its effects on the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), a marker of necroptosis. They observed that piperlongumine inhibited the phosphorylation of RIPK1 at the activation residue Ser166 in cell lines. Additionally, piperlongumine exhibited anti-inflammatory effects in a mouse model of systemic inflammatory response syndrome (SIRS) induced by tumor necrosis factor α (TNFα). It prevented decreases in body temperature and improved survival in the SIRS mice.

The study concluded that piperlongumine is a potent inhibitor of necroptosis, effectively preventing the phosphorylation of RIPK1 and demonstrating anti-necroptotic effects at concentrations that are safe for human cells in vitro. The findings suggest that piperlongumine may have clinical translational value in the treatment of diseases associated with excessive necroptosis, including SIRS.