Influence of the multidrug transporter inhibitors on the activity of Kv1.3 voltage-gated potassium channels.
Using the whole-cell patch-clamp technique, the influence of selected multidrug resistance modulators, both plant-derived compounds and derivatives on the activity of voltage-gated potassium channels Kv1.3 was investigated. Twelve compounds with phenolic and terpenic structures were tested: the stilbenes piceatannol (1) and its tetramethoxy (2) and tetracetoxy (3) derivatives, the flavonoids naringenin (4) and its methylated derivatives: naringenin-4',7-dimethylether (5) and naringenin-7-methylether (6), and aromadendrin (7), the coumarins esculetin (8) and scopoletin (9) and ent-abietane diterpenes, helioscopinolide B (10) and its 3beta-acetoxy derivative (11) and helioscopinolide E (12). The studies were performed on a model system with Kv1.3 channels endogenously expressed in human T lymphocytes. Obtained data provide evidence that compounds 2, 5 and 6 applied at 30 microM inhibited the amplitude of recorded currents to 31%, 4% and 29% of its control value, respectively. On the other hand, compounds 3, 4, 7-12 (at 30 microM) and compound 1 (at 40 microM) did not affect significantly the channel activity. These results indicate that some methoxy-derivatives of the tested compounds are effective inhibitors of Kv1.3 channels. Since the inhibition of Kv1.3 channels may inhibit the proliferation of prostate, breast and colon cancer cells expressing these channels, the channel inhibitors may exert an antiproliferative action. This action combined with a simultaneous modulation of the multidrug resistance may be significant for a potential application of these compounds in cancer chemotherapy.
Wroclaw Medical University, Department of Biophysics, ul. Chalubinskiego 10, Wroclaw, Poland. ateiss@biofiz.am.wroc.pl
A
A
Teisseyre
N
N
Duarte
M-J U
MJ
Ferreira
K
K
Michalak
D049109:Cell Proliferation / Q000187:drug effects; D028481:Euphorbia / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D051664:Kv1.3 Potassium Channel / Q000187:drug effects* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000302:isolation & purification / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism; D013729:Terpenes / Q000302:isolation & purification / Q000494:pharmacology*
D051664:Kv1.3 Potassium Channel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010636:Phenols; D013729:Terpenes