Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo

Abstract

FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anti-cancer agent in multiple animal models. Our published work indicates that the anti-cancer effects of FTY720 do not depend on actions at S1P receptors, but instead stem from FTY720’s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720’s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…The currently known drug targeting S1P is FTY720 (Fingolimod), which is an analog of sphingosine and functions as S1PR agonist. However, while FTY720 phosphorylated by SPHK2 to form FTY720‐phosphate (FTY720‐p) was suggested to a functional antagonist of S1PR1 through binding to S1PR1 and induces internalization and degradation, leading to sequestration of thymocytes and lymphocytes from secondary lymphoid organs thereby reducing inflammation 2, 5, 50, 51. FTY720 demonstrates anti‐cancer properties and may have a potential in cancer treatment 52, 53.…”

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

“…These results indicate that FTY720 and SH-BC-893 induce vacuolation by mislocalizing PIKfyve, leading to generation of the membrane-anchored lipid PI(3,5)P 2 in a compartment separate from its transmembrane effector protein, TRPML1. Ceramide, FTY720, and SH-BC-893 trigger nutrient transporter loss by activating PP2A ( Figure 5, A and B) (18,20,27,45,46). Activation of PP2A by sphingolipids is specific, as dihydroceramide, which differs from ceramide by a single saturated bond, fails to activate PP2A, does not kill cells, and does not trigger transporter loss or vacuolation ( Figure 5A and Supplemental Figure 5A) (46,47).…”

“…The conformationally constrained FTY720 analog SH-BC-893, in contrast, could be used therapeutically, as it does not activate S1P 1 in reporter cells ( Figure 1, A and B). Moreover, neither SH-BC-893 nor its phosphate triggers lymphocyte sequestration, an S1P 1 -dependent effect (27). Importantly, SH-BC-893 still triggers the selective internalization of amino acid (4F2HC, also known as SLC3A2, or ASCT2, also known as SLC1A5) and glucose (GLUT1, also known as SLC2A1) transporters (17, 27) ( Figure 1, C and D).…”

“…Data are representative of at least 3 independent experiments. 4 0 9 0 jci.org Volume 126 Number 11 November 2016 in the heart (22,27,28). The conformationally constrained FTY720 analog SH-BC-893, in contrast, could be used therapeutically, as it does not activate S1P 1 in reporter cells ( Figure 1, A and B).…”

Topical Application of Fingolimod Perturbs Cutaneous Inflammation

“…The precise mechanisms underpinning its effect are still to be determined; however, with documentation that fingolimod inhibits other signal transduction pathways such as SK-1 (37,53), ceramide kinase (54), 14-3-3 protein (55), acid sphingomyelinase (56), and phospholipase A 2 (57), efforts to identify them and then chemically modify the drug to generate clinically relevant analogues is warranted. To this end, Chen et al (70) recently described azacyclic fingolimod analogues that fail to activate S1P 1 and S1P 3 receptors in vivo (such that the lymphopenia-and bradycardia-inducing properties are avoided) but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Thus, designing analogues for absorption into the skin to treat allergic inflammation is potentially possible and deserves further investigation.…”