NAP1051, a Lipoxin A4 Biomimetic Analogue, Demonstrates Antitumor Activity Against the Tumor Microenvironment

Abstract

Resolving tumor-associated inflammation in the tumor microenvironment (TME) may promote antitumor effects. Lipoxin A4 (LXA4) is a short-lived endogenous bioactive lipid with potent anti-inflammatory and pro-resolving properties. Here, a biomimetic of LXA4, NAP1051, was shown to have LXA4-like in vitro properties and antitumor activity in colorectal cancer xenograft models. NAP1051 inhibited neutrophil chemotaxis toward fMLP and dose-dependently promoted dTHP-1 efferocytosis which was equipotent to aspirin-triggered lipoxin A4 (ATLA). In dTHP-1 cells, NAP1051 induced strong phosphorylation on ERK1/2 and AKT similar to formyl peptide receptor 2 (FPR2/ALX) agonists. In two mouse xenograft colorectal cancer models, NAP1051 significantly inhibited tumor growth when given orally at 4.8 to 5 mg/kg/day. Flow cytometric analyses showed that NAP1051 reduced splenic and intratumoral neutrophil and myeloid-derived suppressor cell populations, which correlated to the antitumor effect. In addition, NAP1051 reduced NETosis in the TME while stimulating T-cell recruitment. Overall, these results show that NAP1051 possesses key lipoxin-like properties and has antitumor activity against colorectal cancer via modulation of neutrophils and NETosis in the TME.

Polarized RPE Secretome Preserves Photoreceptors in Retinal Dystrophic RCS Rats

“…While Binet et al proposed that NETs can facilitate elimination of diseased senescent vasculature as a protective mechanism, chronic NETosis overactivation probably results in further destruction of the retinal vasculature. This is corroborated in studies demonstrating that NETosis contributes to the chronic inflammatory microenvironment of colorectal tumors [ 76 ]. In addition to infiltrating neutrophils in retinal vasculature, Müller cells may be responsible for PAD4 and CitH3 expression in the ONL and OS due to their known expression of PAD4 during reactive gliosis [ 77 ].…”

Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development

“…The pro-resolving lipoxins primarily exert their pro-resolving effects by binding to GPR32 on phagocytes and enhance their ability to phagocyte zymosan and apoptotic neutrophils ( Krishnamoorthy et al, 2010 ). Due to the pro-resolving functions of LXA4 ( Serhan et al, 1993 ), a stable LXA4 analogue, NAP1051 with a longer half-life has been developed ( Dong et al, 2021 ). Like LXA4, this analogues inhibits neutrophil migration, and induce apoptosis of neutrophils, leading to a general resolving function.…”

Uncovering mechanisms of brain inflammation in Alzheimer's disease with APOE4: Application of single cell‐type lipidomics

“…Analogs of LXs have been developed to overcome this limitation and supplement the endogenous LXs. LX analogs have been shown to decrease neutrophil infiltration and promote the activation of macrophages to clear debris 275 . Using these platform technologies, more potent and druggable candidates can be developed through optimization to facilitate the efforts of developing therapeutics for AD.…”

“…LX analogs have been shown to decrease neutrophil infiltration and promote the activation of macrophages to clear debris. 275 Using these platform technologies, more potent and druggable candidates can be developed through optimization to facilitate the efforts of developing therapeutics for AD. Lastly, HDL mimetics that can induce ABCA1 activity promise to clear intracellular accumulated lipids and lipid byproducts.…”