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

Autor: Kabir Ahluwalia, Mark S. Humayun, Stan G. Louie, Zeyang Li, Tiange Dong, Tracey Lin, Eunjeong Yoo, Isaac Asante, Malika Salimova, Nicos A. Petasis, Hua Pei, Andrew Mead, Priyal Dave, Eugene Zhou, Alan L. Epstein, Brandon Ebright
Rok vydání: 2021
Předmět:
Zdroj: Molecular Cancer Therapeutics. 20:2384-2397
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.mct-21-0414
Popis: 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.
Databáze: OpenAIRE
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