Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines

Marta Reyes Corral, Naja M. Sørensen, Christopher Thrasivoulou, Prokar Dasgupta, Jonathan F. Ashmore, Aamir Ahmed

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
112 Downloads (Pure)


Class II antiarrhythmics or β-blockers are antisympathetic nervous system agents that act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca2+i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed β-blockers (atenolol, metoprolol, propranolol, and sotalol), on Ca2+i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines). We discovered that only propranolol activated free Ca2+i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranolol-induced Ca2+i release was significantly inhibited by the chelation of extracellular calcium with ethylene glycol tetraacetic acid (EGTA) and by dantrolene, an inhibitor of the endoplasmic reticulum (ER) ryanodine receptor channels, and it was completely abolished by 2-aminoethoxydiphenyl borate, an inhibitor of the ER inositol-1,4,5-trisphosphate (IP3) receptor channels. Exhaustion of ER stores with 4-chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/ER Ca2+ ATPase inhibitor, precluded the propranolol-induced Ca2+i release. Finally, preincubation of cells with sotalol or timolol, nonselective blockers of β-adrenoceptors, also reduced the Ca2+i release activated by propranolol. Our results show that different β-blockers have differential effects on whole-cell currents and free Ca2+i release and that propranolol activates store-operated Ca2+i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP3. The differential action of class II antiarrhythmics on Ca2+i release may have implications on the pharmacology of these drugs.
Original languageEnglish
Pages (from-to)152-162
Number of pages11
JournalThe Journal of pharmacology and experimental therapeutics
Issue number1
Early online date18 Mar 2019
Publication statusPublished - 1 Apr 2019


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