Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. Our group has shown that PP2A activity is reduced in acute myeloid leukemia (AML), and that restoration of PP2A activity in AML cells blocks proliferation, induces caspase-dependent apoptosis, and affects AKT and ERK1/2 activity. It has been proposed that FTY720 suppress PP2A activity by directly interacting with PP2AA-C dimers, and possibly interfering with the SET-PP2A interplay. Reactivation of PP2A by FTY720 in vivo restricts leukemogenesis in different types of hematological malignancies; however, its antitumor effects in AML remain underexplored. Here, we developed lipid nanoparticles (LN) encapsulating FTY720, and evaluated its pharmacokinetic profile and biodistribution in mice, and its antileukemic effects in AML in vitro and in vivo. FTY720-LN show suitable size (around 210 nm) and encapsulation efficiency (nearly 75%) for the oral and intravenous administration of the compound. Blood concentration of FTY720 decreased rapidly 2 hours after the intravenous administration of FTY720-LN; however, orally administered LN provided both a sustained release of the drug over four days and a high distribution in tissues, significantly increasing the accumulation of FTY720 in spleen, compared to the administration of the same dose of FTY720 solution and intravenous administration of FTY720-LN. In vitro studies revealed that FTY720 and FTY720-LN restore PP2A phosphatase activity in AML cells, leading to cell growth arrest, induction of caspase-dependent apoptosis and decrease in phosphorylation of PP2A targets AKT and ERK. Moreover, in vivo daily intraperitoneal administration of FTY720 in RAG2−/− γc−/− mice bearing an AML xenograft tumor reduced significant tumor growth. Of note, oral administration of FTY720-LN every three days was as efficient in reducing AML xenograft tumor growth as a daily oral administration of FTY720. These results provide the first evidence for the potential use of lipid nanoparticles encapsulating FTY720 as a therapeutic agent in AML.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.