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

Pin-Yen Liu; Wei-Ting Chang; Sheng-Nan Wu

doi:10.3390/ijms21218078

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

Int J Mol Sci. 2020 Oct 29;21(21):8078. doi: 10.3390/ijms21218078.

Authors

Pin-Yen Liu^{1

2}, Wei-Ting Chang^{2

3

4}, Sheng-Nan Wu^{5

6}

Affiliations

¹ Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
² Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
³ Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 710, Taiwan.
⁴ Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71005, Taiwan.
⁵ Department of Physiology, National Cheng Kung University Medical College, Tainan 704, Taiwan.
⁶ Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 704, Taiwan.

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 (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).

Keywords: M-type potassium current; delayed-rectifier potassium current; erg-mediated potassium current; heart cell; pituitary cell; ribociclib; voltage hysteresis.

MeSH terms

Action Potentials
Aminopyridines / pharmacology*
Animals
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Delayed Rectifier Potassium Channels / antagonists & inhibitors*
ERG1 Potassium Channel / antagonists & inhibitors*
Pituitary Neoplasms / drug therapy*
Pituitary Neoplasms / metabolism
Pituitary Neoplasms / pathology
Purines / pharmacology*
Tumor Cells, Cultured

Substances

Aminopyridines
Delayed Rectifier Potassium Channels
ERG1 Potassium Channel
Purines
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
ribociclib