State-dependent block of voltage-gated sodium channels by the casein-kinase 1 inhibitor IC261.
Background and Purpose IC261 (3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one) has previously been introduced as an isoform specific inhibitor of casein kinase 1 (CK1) causing cell cycle arrest or cell death of established tumor cell lines. However, it is reasonable to assume that not all antitumor activities of IC261 are mediated by the inhibition of CK1. Meanwhile there is growing evidence that functional voltage-gated sodium channels are also implicated in the progression of tumors as their blockage suppresses tumor migration and invasion of different tumor cell lines. Thus, we asked whether IC261 functionally inhibits voltage-gated sodium channels. Experimental Approach Electrophysiological experiments were performed using the patch-clamp technique at human heart muscle sodium channels heterologously expressed in human TsA cells. Key Results IC261 inhibits sodium channels in a state-dependent manner. IC261 does not interact with the open channel and has only a low affinity for the resting state of the hNav1.5 (human voltage-gated sodium channel; Kr: 120 μM). The efficacy of IC261 strongly increases with membrane depolarisation, indicating that the inactivated state is an important target. The results of different experimental approaches finally revealed an affinity of IC261 to the inactivated state between 1 and 2 μM. Conclusion and Implications IC261 inhibits sodium channels at a similar concentration necessary to reduce CK1δ/ε activity by 50% (IC50value 1 μM). Thus, inhibition of sodium channels might contribute to the antitumor activity of IC261.
Department of Anesthesiology, University Hospital of Ulm, Albert-Einstein-Allee 23, D-89075, Ulm, Germany. karl.foehr@uniklinik-ulm.de.
Karl J
KJ
Föhr
Department of General and Visceral Surgery, University Hospital of Ulm, Albert-Einstein-Allee 23, D-89081, Ulm, Germany.
Uwe
U
Knippschild
Department of Anesthesiology, University Hospital of Ulm, Albert-Einstein-Allee 23, D-89081, Ulm, Germany.
Anna
A
Herkommer
Institute of General Physiology, University of Ulm, Albert-Einstein-Allee 11, D-89081, Ulm, Germany.
Michael
M
Fauler
Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118, Kiel, Germany.
Christian
C
Peifer
Department of Anesthesiology, University Hospital of Ulm, Albert-Einstein-Allee 23, D-89075, Ulm, Germany.
Michael
M
Georgieff
Department of Anesthesiology, University Hospital of Ulm, Albert-Einstein-Allee 23, D-89075, Ulm, Germany.
Oliver
0000-0002-2214-6153
O
Adolph
D047389:Casein Kinase I / Q000037:antagonists & inhibitors*; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000502:physiology*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology*
C411652:IC 261; D007211:Indoles; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D010696:Phloroglucinol; D047389:Casein Kinase I
Cytotoxicity; IC261; Patch clamp; Sodium channel; Tumor growth