AUTHOR=So Edmund Cheung , Liu Ping-Yen , Lee Chien-Ching , Wu Sheng-Nan 

TITLE=High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01163

DOI=10.3389/fphar.2019.01163

ISSN=1663-9812

ABSTRACT=<p>Carfilzomib (CFZ, Kyprolis<sup>®</sup>) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH<sub>3</sub>, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K<sup>+</sup> current (<italic>I</italic><sub>K(DR)</sub>) in a time-, state-, and concentration-dependent manner in pituitary GH<sub>3</sub> cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of <italic>I</italic><sub>K(DR)</sub> in these cells was 0.33 µM, which is similar to the IC<sub>50</sub> value (0.32 µM) used for its efficacy on inhibition of <italic>I</italic><sub>K(DR)</sub> amplitude. Recovery from <italic>I</italic><sub>K(DR)</sub> block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K<sup>+</sup> current, another type of K<sup>+</sup> current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH<sub>3</sub> cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of <italic>I</italic><sub>K(DR)</sub> remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane K<sub>V</sub> channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar <italic>in vivo</italic> findings occur.</p>