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).
Highlights
Ribociclib (RIB, LE011, Kisqali®) is an oral small-molecule inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex
We evaluated the possible effect of RIB on IK(erg) in HL-1 cardiomyocytes
This study revealed that RIB could decrease IK(erg) and IK(DR), the ionic mechanisms that do not appear to have a causal link to its suppression of CDK-4/6 activity
Summary
Ribociclib (RIB, LE011, Kisqali®) is an oral small-molecule inhibitor of cyclin-dependent kinase-4/6 (CDK-4/6) complex. The erg-mediated K+ current (IK(erg)) is known to be encoded by three different subfamilies of KCNH, and it can give rise to the pore-forming α–subunit of erg-mediated K+ (i.e., Kerg or KV11) channels [16] This current is regarded as constituting the cloned counterpart of the rapidly activating delayed-rectifying K+ currents in heart cells [17]. We examined whether RIB produces any perturbations of the various types of ionic currents through the membranes of excitable cells, including IK(erg), delayed-rectifier K+ current (IK(DR)), M-type K+ current (IK(M)), and hyperpolarization-activated cation current (Ih) found in pituitary tumor (GH3) cells. The importance of RIB-induced inhibition of CDK-4/6 activity seems to be overestimated, notwithstanding the presence of the CDK complex in the cytosol of pituitary tumor cells or heart cells [9,27,28,29]
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