Abstract
The formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation. More recently, FPR1 has been shown to be expressed in different types of cancer and in this context, plays a significant role in their expansion, resistance and recurrence. ICT12035 is a selective and potent (30 nM in calcium mobilisation assay) small molecule FPR1 antagonist. Here, we demonstrate the efficacy of ICT12035, in a number of 2D and 3D proliferation and invasion in vitro assays and an in vivo model. Our results demonstrate that targeting FPR1 by a selective small molecule antagonist, such as ICT12035, can provide a new avenue for the treatment of cancers.
Highlights
The formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation
Necrotised cells release many of their cytoplasmic molecules, which includes annexin A1 (ANXA1) protein, into the extracellular m ilieu[30,41,42,43,44]
ANXA1 appears to have a distinct tumour promoting effect by binding and activating FPR1, the expression of which is shown to be elevated in many tumours[13,16,17,18,19,20,21,22]
Summary
The formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation. FPR1, which is the most common of the three, is expressed on a variety of leucocytes including monocytes and macrophages2,3, neutrophils[2,3], immature dendritic c ells[4], natural killer c ells[5], and T c ells[6] Leukocytes respond after their FPR1 receptors are activated by molecules which are released at the site of infection as a result of bacterial or tissue necrosis and d amage[7,8]. Vecchi and Goulart have shown that immunosuppressant cyclosporine A, which is a weak antagonist of FPR1 (IC50 = 2–4 μM in calcium mobilisation assay27), retards tumour growth and invasiveness in a breast cancer in vivo m odel[21]. We show that ICT12035 reduces proliferation and invasion of cancer cell lines in a number of 2D and 3D assays, and retards growth of tumours in an in vivo xenograft model
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