NAP1051, a Lipoxin A4 Biomimetic Analogue, Demonstrates Antitumor Activity Against the Tumor Microenvironment
- Mol Cancer Ther. 2021 Dec;20(12):2384-2397. doi: 10.1158/1535-7163.MCT-21-0414.
- 1. School of Pharmacy, University of Southern California, Los Angeles, California.
- 2. HD Biosciences, Wuxi Apptec, San Diego, California.
- 3. Department of Ophthalmology, University of Southern California, Los Angeles, California.
- 4. Department of Chemistry, University of Southern California, Los Angeles, California.
- 5. Department of Pathology, University of Southern California, Los Angeles, California.
- 6. School of Pharmacy, University of Southern California, Los Angeles, California. [email protected].
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.