Purpose: Sphingosine-1-phosphate (S1P) is a pleotropic bioactive lipid mediator involved in the pathogenesis of inflammation and cancer. FTY720 is a “functional antagonist” of S1P by binding and induces the internalization and degradation of S1P receptors. Indeed, FTY720 was shown to have antitumor activity in several tumor models, while whether its immune-suppressive activity promotes or inhibits tumor growth is still unclear. In this study, we explored the antitumor activity of FTY720 in various cancer cells and its underlying mechanisms.
Experimental Procedures: We analyzed the antiproliferative activity of FTY720 in nearly 30 human cancer cell lines and 6 mouse cancer cell lines. Human colon cancer cells SW620 and mouse breast cancer cells 4T1, which are sensitive to FTY720, were selected and used for in vivo study. SW620 was subcutaneously inoculated into Balb/c nude mice and 4T1 were in situ inoculated into immune-competent Balb/c mice. Mice was administrated intraperitoneally with low dose (0.5 mg/kg/d) and high dose (5 mg/kg/d) of FTY720. Tumor volume and body weight were measured every 3 days. After 3 weeks, the mice were sacrificed, and the tumor was removed and weighed, and kept for further analysis. The signaling pathway involved in S1P pathway and neovascularization were analyzed. In addition, the pharmacokinetics of FTY720 was also determined in mice. The effect of FTY720 on angiogenesis was also analyzed at cellular level, as well as the gene expression in HUVEC cells.
Summary: FTY720 showed potent antiproliferative activity across various cancer cell lines. The IC50 for SW620 and 4T1 was 3.71 μM and 3.38 μM respectively, which were most sensitive. In animal study, both low-dose and high-dose FTY720 dramatically inhibited the tumor growth in SW620 xenograft model, while only high-dose FTY720 inhibited tumor growth in 4T1 xenograft model. Since the serum concentration of FTY720 was much lower than its cytotoxicity at low dose, we thus propose the anti-umor activity of FTY720 may due to its antiangiogenic activity. Moreover, the antitumor activity of FTY720 was much lower for 4T1 as compared to SW620 xenograft model, which possibly is caused by its immune-suppressive activity as it depleted the circulating lymphocytes. Besides, FTY720 dramatically inhibited neovascularization in tumor tissues. The half-life and AUClast are good for FTY720 in mice. FTY720 inhibited new vessel formation at cellular level. In addition, the microarray data showed the low-dose FTY720 (100 nM) induced the alteration of a few genes’ expression.
Conclusion: FTY720 has potent antitumor activity both in vitro and in vivo, the mechanism of which is associated with proapoptotic, antiangiogenic and anti-inflammatory activities. The immune-suppressive activity of FTY720 may limit the antitumor activity in immune-competent individuals. This study provides a comprehensive understanding of the immune-suppressant FTY720 in antitumor.
Note: This abstract was not presented at the conference.
Citation Format: Zuoquan Xie, Xiaoxu Chen, Hui Xu, Jing Ai, Meiyu Geng. In vitro and In vivo antitumor activity of immune suppressant FTY720 [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A83.