Characterization of the Synergistic Inhibition of IK(erg) and IK(DR) by Ribociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor

Abstract

Ribociclib (RIB, LE011, Kisqali®), an orally administered inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex, is clinically effective for the treatment of several malignancies, including advanced breast cancer. However, information regarding the effects of RIB on membrane ion currents is limited. In this study, the addition of RIB to pituitary tumor (GH3) cells decreased the peak amplitude of erg-mediated K+ current (IK(erg)), which was accompanied by a slowed deactivation rate of the current. The IC50 value for RIB-perturbed inhibition of deactivating IK(erg) in these cells was 2.7 μM. In continued presence of μM RIB, neither the subsequent addition of 17β-estradiol (30 μM), phorbol 12-myristate 13-acetate (10 μM), or transforming growth factor-β (1 μM) counteracted the inhibition of deactivating IK(erg). Its presence affected the decrease in the degree of voltage-dependent hysteresis for IK(erg) elicitation by long-duration triangular ramp voltage commands. The presence of RIB differentially inhibited the peak or sustained component of delayed rectifier K+ current (IK(DR)) with an effective IC50 of 28.7 or 11.4 μM, respectively, while it concentration-dependently decreased the amplitude of M-type K+ current with IC50 of 13.3 μM. Upon 10-s long membrane depolarization, RIB elicited a decrease in the IK(DR) amplitude, which was concomitant with an accelerated inactivation time course. However, the inability of RIB (10 μM) to modify the magnitude of the hyperpolarization-activated cation current was disclosed. The mean current–voltage relationship of IK(erg) present in HL-1 atrial cardiomyocytes was inhibited in the presence of RIB (10 μM). Collectively, the hyperpolarization-activated cation current was observed. RIB-mediated perturbations in ionic currents presented herein are upstream of its suppressive action on cytosolic CDK-4/6 activities and partly participates in its modulatory effects on the functional activities of pituitary tumor cells (e.g., GH3 cells) or cardiac myocytes (e.g., HL-1 cells).

Effective Perturbations on the Amplitude and Hysteresis of Erg-Mediated Potassium Current Caused by 1-Octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6(undecyloxy)hexyl]amino]-octanoate (SM-102), a Cationic Lipid

“…The intriguing phenomenon of voltage-dependent hysteresis of ionic currents including I K(erg) has been proposed to play roles in influencing cell behaviors of varying types of electrically excitable cells [28][29][30][31][32]. In keeping with previous observations [28,29], the I K(erg) present in GH 3 or MA-10 cells did undergo voltage-dependent hysteresis, as it was activated by a long isosceles-triangular ramp voltage.…”

“…The intriguing phenomenon of voltage-dependent hysteresis of ionic currents including I K(erg) has been proposed to play roles in influencing cell behaviors of varying types of electrically excitable cells [28][29][30][31][32]. In keeping with previous observations [28,29], the I K(erg) present in GH 3 or MA-10 cells did undergo voltage-dependent hysteresis, as it was activated by a long isosceles-triangular ramp voltage. Such hysteresis may result from a mode shift, because the voltage sensitivity of the gating charge movement is thought to rely on the previous state of the channel owing to the so-called dynamic voltage dependence.…”

“…Such a hyperpolarizing voltage pulse was noticed to elicit an instantaneous current followed by a voltage-and time-dependent decay of the K + inward current, as reported elsewhere [17,20,28]. This type of ionic current, which was effectively inhibited by either E-4031 or glyceryl nonivamide (GLNVA), has been identified to be an erg-mediated K + current (I K(erg) ) [17,18,20,29]. For example, 1 min after GH 3 were exposed to 10 µM E-4031, the peak or sustained I K(erg) , respectively, decreased to 42 ± 6 or 21 ± 8 pA (n = 7) from control values of 177 ± 42 or 49 ± 9 pA (n = 7).…”

“…The voltage-dependent hysteresis of I K(erg) has been previously characterized in GH 3 cells [28,29], and the hysteretic strength of different types of ionic currents has been recently disclosed to exercise an important impact on electrical behaviors of electrically excitable cells [29][30][31]. Analyses of hysteretic behavior have proven to be a useful tool in studies of ion channels [31,32].…”

Editorial to the Special Issue “Electrophysiology”

“…Its presence also differentially inhibited the peak and sustained components of delayed rectifier K + currents in these cells. RIB-mediated perturbations on ionic currents tend to be upstream of its suppressive action on cytosolic CDK-4/6 activities [ 6 ].…”