Characterization of the synergistic inhibition of i_k(Erg) and i_k(dr) by ribociclib, a cyclin-dependent kinase 4/6 inhibitor

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 (I_K(erg)), which was accompanied by a slowed deactivation rate of the current. The IC₅₀ value for RIB-perturbed inhibition of deactivating I_K(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 I_K(erg). Its presence affected the decrease in the degree of voltage-dependent hysteresis for I_K(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 (I_K(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 I_K(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 I_K(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).