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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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).

Original languageEnglish
Article number8078
Pages (from-to)1-17
Number of pages17
JournalInternational journal of molecular sciences
Issue number21
Publication statusPublished - 2020 Nov 1

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


Dive into the research topics of 'Characterization of the synergistic inhibition of ik(Erg) and ik(dr) by ribociclib, a cyclin-dependent kinase 4/6 inhibitor'. Together they form a unique fingerprint.

Cite this