Sphingosine kinase 2 inhibitor ABC294640 suppresses neuronal excitability and inhibits multiple endogenously and exogenously expressed voltage-gated ion channels in cultured cells

Sphingolipids regulate multiple cellular processes, including proliferation, Autophagy, and Apoptosis. Sphingosine kinases, the key enzymes in the metabolism of sphingolipids, are overexpressed in many cancers, making them important targets for the development of antitumor drugs. ABC294640 is a selective sphingosine kinase 2 (SK2) inhibitor that shows good antitumor activity in vitro. One phase I clinical study of ABC294640 reported that ABC294640 caused a variety of neurological disorders. The mechanism of these phenomena, however, remains unclear. In the present study, we used in vitro cell experiments to test the effects of ABC294640 on the nervous system. We found that ABC294640 suppressed the firing of action potentials in cultured hippocampal neurons from neonatal mice and inhibited endogenous sodium, potassium, and calcium currents in both cultured neurons and SH-SY5Y cells. In addition, we tested four types of human voltage-gated potassium channels transiently expressed in HEK293T cells. All were inhibited by ABC294640, of which K_V4.2 and K_V1.4 were more sensitive than BK and K2P2.1. The effect of ABC294640 on ion channels was different from another SK2 inhibitor K145 and was not affected by S1P. The fast onset and recovery of the inhibition indicated that ABC294640 was likely to inhibit ion channels by acting directly on channel proteins, rather than by inhibiting SK2. These results revealed the mechanism by which ABC294640 interferes with the nervous system. To develop future antitumor drugs, researchers should modify the structure of ABC294640 to avoid its effects on ion channels or should develop compounds that target SK2 or downstream molecules.