Journal
ACTA PHARMACEUTICA
Volume 71, Issue 2, Pages 317-324Publisher
HRVATSKO FARMACEUTSKO DRUSTOV (HFD)-CROATION PHARMACEUTICAL SOC
DOI: 10.2478/acph-2021-0017
Keywords
erfenadine; inward rectifier potassium channels; phosphatidylinositol 4,5-bisphosphate; cationic amphiphilic drugs
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Funding
- SEP-Conacyt grants [CB-2010-01-153394, CB-2013-01-220546]
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Terfenadine, a second-generation H1-antihistamine known for its potential severe side effects, has recently gained attention for its anticancer properties. Researchers found that terfenadine inhibits Kir2.x channels by affecting their interaction with PIP2, which may be a mechanism for its antitumor effects.
Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC50 = 1.06 +/- 0.11 mu mol L-1) compared to Kir2.1 channels (IC50 = 27.8 +/- 4.8 mu mol L-1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC50 = 13.0 +/- 2.9 mu mol L-1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfenadine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.
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