Liposome mitigation of curcumin inhibition of cardiac potassium delayed-rectifier current

Lawrence Helson,¹ George Shopp,² Annie Bouchard,³ Muhammad Majeed<sup>4

1</sup>SignPath Pharma, Quakertown, PA, USA; ²Shopp Nonclinical Consulting, Boulder, CO, USA; ³IPS Therapeutique Inc, Sherbrooke, Quebec, Canada; ⁴Sabinsa Inc, Princeton, NJ, USA

Background: The duration of the QT interval on the standard electrocardiogram (ECG) is measured from the beginning of the QRS complex (depolarization of the cardiac myocyte) to the end of the T-wave (completion of the repolarization phase of the cardiac myocyte). Repolarization is a result of currents generated by the outward flow of K⁺ through the K⁺ channels. Obstruction of ion flow in the channel leads to delayed repolarization, evidenced by a prolonged QT interval. Clinically, this is known as the long QT syndrome (LQTS), which, when expressed, can lead to severe cardiac arrhythmias and sudden death. Obstruction of K⁺ ion flow can result from gene mutations (eg, the human ether-a-go-go-related gene [hERG]) resulting in phenotypic abnormalities in K⁺ channels and/or common structurally diverse drugs. These gene abnormalities or drug-induced changes result in decreased cardiac delayed-rectifier K⁺ current (I_Kr, or KV11.1) in congenital or acquired LQTS, respectively. Increased risk of LQTS is a major drug development hurdle, and many drugs have been withdrawn during preclinical development, assigned black box warnings following approval, or withdrawn from the market. Autosomal recessive or dominant LQTS based upon 500 possible mutations in ten different genes coding for K⁺ channels has an incidence of 1:3000 or about 100,000 persons in the USA. Prolonged QT intervals or risk of LQTS occurs in 2.5% of the asymptomatic US population. The probability of cardiac death in patients with asymptomatic congenital LQTS who are concomitantly medicated with LQTS-inducing drugs appears to have increased.
Methods: E-4031 (methanesulfanalide), terfenadine (Seldane^®), curcumin, liposomal curcumin, empty liposomes, empty liposomes vortexed with E-4031, or terfenadine and empty liposomes vortexed with curcumin were assayed for their effects on the K⁺-selective I_Kr tail current inhibition using human embryonic kidney (HEK 293) cells stably transfected with the hERG gene via the whole-cell manual patch clamp technique.
Results: E-4031, terfenadine, and curcumin inhibit I_Kr channel following nM-to-µM exposures. Empty liposomes had no effect on I_Kr. Both the liposomal curcumin formulation and vortexed mixtures of empty liposomes and curcumin prevented the I_Kr inhibitory effect of curcumin in a dose-dependent manner. Empty liposomes vortexed with E-4031 prevented the effect of E-4031 to a lesser extent, while empty liposomes vortexed with terfenadine did not alter its I_Kr inhibitory activity.
Conclusion: Curcumin causes an inhibition of the hERG tail current density. The liposomal curcumin formulation, as well as a mixture of empty liposomes with curcumin or with E-4031, blocked drug-induced IKr inhibition. However, empty liposomes mixed with terfenadine did not alter terfenadine’s I_Kr inhibitory effects. The liposomes protected against the inhibitory effect of some compounds on the K⁺-selective I_Kr current, independent of their potency.

Keywords: torsade de point, hERG, ion channel