Sphingosine Kinase 2 Inhibitor ABC294640 Suppresses Neuronal Excitability and Inhibits Multiple Endogenously and Exogenously Expressed Voltage-Gated Ion Channels in Cultured Cells

Abstract

Sphingolipidsregulatemultiplecellularprocesses, including proliferation,autophagy, andapoptosis.Sphingosinekinases,thekeyenzymesinthemetabolismofsphingolipids,areoverexpressedinmanycancers,makingthemimportanttargetsforthedevelopmentof antitumordrugs.ABC294640isaselectivesphingosinekinase2(SK2)inhibitorthatshowsgoodantitumoractivityinvitro. One phaseIclinicalstudyofABC294640reportedthatABC294640causedavarietyofneurologicaldisorders. The mechanismofthesephenomena, however, remainsunclear.Inthepresentstudy,weusedinvitrocellexperimentstotesttheeffectsofABC294640onthenervoussystem.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.Inaddition,wetestedfourtypesofhuman voltage-gated potassium channelstransientlyexpressedinHEK293Tcells.AllwereinhibitedbyABC294640,ofwhichKV4.2andKV1.4weremoresensitivethanBKandK2P2.1.TheeffectofABC294640onionchannels was differentfromanotherSK2inhibitorK145and was notaffectedbyS1P.Thefastonsetandrecoveryoftheinhibitionindicated thatABC294640 was likelytoinhibitionchannelsbyactingdirectlyonchannelproteins,ratherthanbyinhibitingSK2.TheseresultsrevealedthemechanismbywhichABC294640 interferes withthenervoussystem.Todevelopfuture antitumordrugs,researchersshouldmodifythestructureofABC294640toavoiditseffectsonionchannelsor should developcompoundsthattargetSK2ordownstreammolecules.