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

• Published in: Molecular cancer therapeutics 2021-12, Vol.20 (12), p.2384-2397
• Main Authors: Dong, Tiange, Dave, Priyal, Yoo, EunJeong, Ebright, Brandon, Ahluwalia, Kabir, Zhou, Eugene, Asante, Isaac, Salimova, Malika, Pei, Hua, Lin, Tracey, Mead, Andrew, Li, Zeyang, Humayun, Mark, Petasis, Nicos A, Epstein, Alan L, Louie, Stan G
• Format: Article
• Language: English
• Subjects: Animals; Biomimetics - methods; Humans; Lipoxins - metabolism; Male; Mice; Mice, Nude; Neoplasms - drug therapy; Transfection; Tumor Microenvironment
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-21-0414

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 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.