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

Abstract

Class II antiarrhythmics or b-blockers are antisympathetic nervous system agents that act by blocking b-adrenoceptors. Despite their common clinical use, little is known about the effects of b-blockers on free intracellular calcium (Ca 21 i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed b-blockers (atenolol, metoprolol, propranolol, and sotalol), on Ca 21 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 Ca 21 i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranololinduced Ca 21 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 (IP 3) receptor channels. Exhaustion of ER stores with 4-chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/ER Ca 21 ATPase inhibitor, precluded the propranolol-induced Ca 21 i release. Finally, preincubation of cells with sotalol or timolol, nonselective blockers of b-adrenoceptors, also reduced the Ca 21 i release activated by propranolol. Our results show that different b-blockers have differential effects on whole-cell currents and free Ca 21 i release and that propranolol activates store-operated Ca 21 i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP 3. The differential action of class II antiarrhythmics on Ca 21 i release may have implications on the pharmacology of these drugs.

Beta‐blockers exert potent anti‐tumor effects in cutaneous and uveal melanoma

“…26 Propranolol induces apoptosis in CM cell lines 19 through non-selective β1 and β2-AR antagonism that may inhibit ERK/MAPK1/3 as well as negatively block the ERK/MAPK pathway by releasing intracellular calcium. 27 Increased intracellular Ca 2+ in CM can induce the WNT signaling cascade, responsible for activating PKC and CamKII. 28 In UM, among the downstream effectors of GNAQ/11, the main function of the second messenger IP3 is to activate PKC by increasing the cytosol calcium levels.…”

“…β‐AR 1, 2, and 3 can activate ERK/MAPK1/3 . Propranolol induces apoptosis in CM cell lines through non‐selective β1 and β2‐AR antagonism that may inhibit ERK/MAPK1/3 as well as negatively block the ERK/MAPK pathway by releasing intracellular calcium . Increased intracellular Ca 2+ in CM can induce the WNT signaling cascade, responsible for activating PKC and CamKII .…”

Ca2+ movement and cytotoxicity induced by the pyrethroid pesticide bifenthrin in human prostate cancer cells

“…Among all the organelles, the endoplasmic reticulum has been shown to be the main Ca 2þ store in most cell types. 30 Thus, the role of the endoplasmic reticulum in bifenthrin-evoked Ca 2þ release in PC3 cells was explored. The BHQ-sensitive endoplasmic reticulum store appears to be the pivotal Ca 2þ store.…”

Dantrolene and ryanodine receptors in COVID‐19: The daunting task and neglected warden

“…Liver inflammation, pleural effusion and bone marrow depression have also been reported as critical adverse effects associated with prolonged use of DTN 1,9 . Long‐term use of a low dose of DTN (<400 mg/day) is relatively safe and not associated with the development of liver injury 10 . Chen et al 11 reported that venous thromboembolism may develop following a large dose of DTN therapy (>400 mg/day) for malignant hyperthermia.…”

“…1,9 Longterm use of a low dose of DTN (<400 mg/day) is relatively safe and not associated with the development of liver injury. 10 Chen et al 11 reported that venous thromboembolism may develop following a large dose of DTN therapy (>400 mg/day) for malignant hyperthermia. The underlying cause of thromboembolism in DTN therapy is because of muscle weakness-induced thrombogenesis.…”